Tricyclic fused heterocycle compounds, process for preparing the same and use thereof

ABSTRACT

Compounds represented by formula (1),  
                 
 
     wherein  
     X is, for example, CH, CH 2 , CHR (wherein R is a lower alkyl group or a substituted lower alkyl group) or CRR′ (wherein R and R′ are the same as the above defined R);  
     Y is, for example, CH, CH 2  or C═O;  
     Z is, for example, O, S, S═O or SO 2 ;  
     U is C or N;  
     R 1  to R 4  are each independently, for example, a hydrogen atom, OR, SR (wherein R is the same as defined above), or an aromatic ring, a substituted aromatic ring or a heterocycle;  
     at least one of R 5  and R 8  is, for example, OH and the remaining of R 5  and R 8  are each independently, for example, a hydrogen atom or OH, optical isomers thereof, conjugates thereof or pharmaceutically acceptable salts thereof are provided. These compounds are characterized in having a wide range of pharmacological actions such as an excellent relaxing action of tracheal smooth muscles, an inhibition of airway hypersensitivity and an inhibition of infiltration of inflammatory cells into the airway and, in addition, high safety.

TECHNICAL FIELD

[0001] The present invention relates to novel tricyclic condensedheterocyclic compounds, their preparation method and uses. The tricycliccondensed heterocyclic compounds of the present invention have a widerange of pharmacological actions such as the relaxing action of trachealsmooth muscles, the inhibition of airway hypersensitivity and theinhibition of infiltration of inflammatory cells into the airway and areuseful as drugs such as antiasthmatic drugs.

BACKGROUND ART

[0002] Heretofore, various cyclic compounds have been proposed as thecompounds useful for asthma and the like. For example, xanthinederivatives such as theophylline and P₂-agonists such as salbutamol,steroids, antiallergic drugs and the like are known.

[0003] Further, various tricyclic condensed heterocyclic compounds areproposed.

[0004] Examples of such prior arts are mentioned below.

[0005]Yakugaku Zasshi, 87,(2), 198-201 (1967) discloses threedihydrodibenz[b,f]oxepin derivatives as the synthetic intermediates of anatural product but no pharmacological action and the like relating tothese compounds are described.

[0006] U.S. Pat. No. 4,104,280 describes that tricyclc condensedheterocyclic compounds containing an oxygen atom or a sulfur atom as theheterocylic atom and a substituent of —CHRCOOH or —CHRCOOCH₃ (wherein Ris a hydrogen atom or a methyl group) on the benzene ring are useful asanti-inflammatory drugs and relaxants.

[0007] European Patent Publication No. 0 011 067 Al suggests thattriclyclic condensed heterocyclic compounds containing a sulfur atom asthe heterocyclic atom and —(CH₂)_(n)-A (wherein n is 0 to 4; and A is aheterocyclic residue) as one substituent on the benzene ring areeffective for asthma, allergy and the like.

[0008] British Patent No. 2,016,466 describes that triclyclic condensedheterocyclic compounds containing an oxygen atom or a sulfur atom as theheterocyclic atom and —CH₂COR (wherein R is OH, NH₂, a C₁₋₅ alkyl groupor the like) as one substituent on the benzene ring are useful asanti-inflammatory drugs.

[0009] German Patent No. 32 03065 discloses that certain types oftriclyclic condensed heterocyclic compounds containing an oxygen atom ora sulfur atom as the heterocyclic atom and various substituents on thebenzene ring have pharmacological actions such as analgesia, sedation,antidepression, antispastic action.

[0010] European Patent Publication No. 0 003 893 discloses thattriclyclic condensed heterocyclic compounds containing oxygen or sulfuras the heterocyclic atom and having —CHR₂COOR₃ (wherein R₂ is a hydrogenatom or a methyl group; and R₃ is a hydrogen atom or —CH₂CH₂OCH₂CH₂OH)as one substituent on the benzene ring have pharmacological actions suchas anti-inflammation, analgesia and pyretolysis.

[0011] German Patent No. 1,302,590 describes tricyclic condensedheterocyclic compounds containing sulfur as the hetero atom and havingvarious substituents on the benzene ring.

[0012] U.S. Pat. No. 4,104,280 teaches that3-hydroxymethyl-benzo[b,f]thiepin containing a sulfur atom as theheterocyclic atom and its derivatives are used in the treatment ofallergic diseases such as allergic asthma.

[0013]Br. J. Pharmac., 82, 389-395 (1984) describes2-hydroxy-methyl-dibenzo[b,f]thiepin-5,5-dioxide which is an antagonistof prostanoids contractile for lung smooth muscles.

[0014]Japanese Pharm. Soc. Bull., 94, 299-307 (1989) suggests that2-(10,11-dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic acid possiblybecomes a clinically useful substance as an anti-inflammatory, analgesicand antipyretic drug since it only has a slight effect on circulatoryorgans and the autonomic nervous system when a considerably large amountis used.

[0015] WO Publication 96/10021 describes antioxidative tricyliccondensed heterocyclic compounds containing oxygen or sulfur as theheterocyclic atom and having various substitutents on the benzene ring.

[0016] WO Publication 96/25927 describes glutamic receptor blockers andcerebral function improving drugs containing oxygen or sulfur as theheterocyclic atom and having various substitutents on the benzene ring.

[0017] WO Publication 97/25985 describes tracheal smooth musclerelaxants having compounds containing oxygen or sulfur as theheterocyclic atom and having various substituents on the benzene ring asthe effective component.

[0018]J. Org. Chem., 61,5818-5822 (1996) and Collection Czechoslov.Chem. Commum., 43, 309 (1978) describe the synthesis of dibenzoxepinsand dibenzothiepins.

[0019]Terahedron, 40, 4245-4252 (1984) and Phytochemistry, 31, (3)1068-1070 (1992) describe dibenzoxepin derivatives derived from anatural substance.

[0020]Chem. Pharm. Bull., 23, (10) 2223-2231 (1975) and Chem. Pharm.Bull., 26, (10) 3058-3070 (1978) describe the synthetic methods ofdibenzothiepin derivatives and the antiemetic action of these compounds.

[0021]J. Chem. Soc. Perkin Trans. 1, 3291-3294 (1991) and J. Med. Chem.,26, 1131-1137 (1983) describe the synthetic methods of dibenzoxepin anddibenzothiepin derivatives and the anti-estrogenic action of thesecompounds.

[0022] As stated above, heretofore, various tricyclic condensedheterocyclic compounds have been disclosed, but they cannot be said tobe sufficient in respect of therapeutic effect, prolonged action, safety(in terms of preventing side effects) when used as therapeutic drugs forairway disorders such as bronchial asthma, acute or chronic bronchitis,pulmonary emphysema and upper esophagitis and the like and lungdiseases, allergic diseases, chronic inflammation and the like. Thus,the development of novel compounds having a broad range ofpharmacological actions including an airway smooth muscle relaxingaction, an inhibition of airway hypersensitivity and an inhibition ofinfiltration of inflammatory cells into the airway and, at the sametime, high safety (reduced side effects) is demanded.

DISCLOSURE OF THE INVENTION

[0023] In view of the above described present situations, the object ofthe present invention is to provide novel compounds which have a widerange of pharmacological actions such as a clinically useful relaxingaction of tracheal smooth muscles, an inhibition of airwayhypersensitivity and an inhibition of infiltration of inflammatory cellsinto the airway.

[0024] The present inventors have found as a result of strenuousinvestigations of tricyclic condensed heterocyclic compounds thatcertain types of tricyclic condensed heterocyclic compounds having an OHgroup, or an OH group and an OR group (wherein R is a hydrogen atom or alower alkyl group) as the substitutent have a wide range ofpharmacological actions such as a relaxation of tracheal smooth muscles,an inhibition of airway hypersensitivity and an inhibition ofinfiltration of inflammatory cells into the airway and, in addition, anexcellent prolonged action and safety, and have completed the presentinvention on the basis of this knowledge. Specifically, the presentinvention relates to the compounds, their preparation method, uses andintermediates described in the following (1) to (25).

[0025] (1) A compound represented by formula (1),

[0026] wherein

[0027] when the X—Y bond is a single bond, X and Y, which may be thesame or different, are each independently any one selected from thegroup consisting of CW₁W₂ (wherein W₁ and W₂, which may be the same ordifferent, are each independently any one of a hydrogen atom, a halogen,a hydroxyl group, a lower alkyl group, a substituted lower alkyl group,a lower alkoxy group, a cycloalkyl group and a cycloalkenyl group), C═O,and C═NOW₃ (wherein W₃ is a hydrogen atom or a lower alkyl group);

[0028] when the X—Y bond is a double bond, X and Y, which may be thesame or different, are each independently CW₄ (wherein W₄ is any one ofa hydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, asubstituted lower alkyl group, a lower alkoxy group and an acyloxygroup);

[0029] Z is any one selected from O, S, S═O and SO₂;

[0030] U is C or N;

[0031] R₁ to R₄, which may be the same or different, are eachindependently any one selected from the group consisting of a hydrogenatom, a lower alkyl group, a substituted lower alkyl group, a cycloalkylgroup, a substituted cycloalkyl group, a lower alkenyl group, asubstituted lower alkenyl group, a lower alkynyl group, a substitutedlower alkynyl group, a halogen, a lower alkylcarbonyl group, asubstituted lower alkylcarbonyl group, a trihalomethyl group, V₁W₅(wherein V₁ is any one of O, S, S═O and SO₂; and W₅ is any one of ahydrogen atom, a lower alkyl group, a substituted lower alkyl group, alower alkylcarbonyl group and a substituted lower alkylcarbonyl group,an acyloxy group and a trihalomethyl group), a nitro group, an aminogroup, a substituted amino group, a cyano group, an acyl group, anacylamino group, a substituted acyl group, a substituted acylaminogroup, an aromatic ring, a substituted aromatic ring, a heterocycle anda substituted heterocycle (when U is N, R₄ does not exist in somecases);

[0032] R₅ to R₈, which may be the same or different, are eachindependently any one selected from the group consisting of a hydrogenatom, a lower alkyl group, a substituted lower alkyl group, a loweralkenyl group, a substituted lower alkenyl group, a lower alkynyl group,a substituted lower alkynyl group, a halogen, a lower alkylcarbonylgroup, a substituted lower alkylcarbonyl group, a trihalomethyl group,V₂W₇ (wherein V₂ is any one selected from O, S, S═O and SO₂; and W₇ isany one selected from a hydrogen atom, a lower alkyl group, asubstituted lower alkyl group, a lower alkylcarbonyl group, asubstituted lower alkylcarbonyl group and a trihalomethyl group), anitro group, an amino group, a substituted amino group, an acylaminogroup, an aromatic ring, a substituted aromatic ring, a heterocycle anda substituted heterocycle;

[0033] provided that at least one of R₅ to R₈ is a hydroxyl group[provided that at least one of R₅, R₇ or R₈ is a hydroxy group when theX—Y bond is CH(C₂H₅)CO and R₆ is a hydroxyl group] when X is CHW₀, CW₀W,or CW₀ (wherein W₀ is any one selected from a lower alkyl group and asubstituted lower alkyl group) and at least one of R,₅ to R₈ is ahydroxyl group and, at the same time, at least one of the other R₅ to R₈is a group of OR (wherein R is any one selected from the groupconsisting of a hydrogen atom, a lower alkyl group, a substituted loweralkyl group, a lower alkylcarbonyl group and a substituted loweralkylsilyl group) when X is other than CHW₀, CW₀W₀ or CW,₀ (wherein W₀is any one selected from a lower alkyl group and a substituted loweralkyl group);

[0034] in addition, when the X—Y is CH₂CH₂, CHBrCH₂, CH₂CO, CHBrCO,CH═CH, CH═COCOCH₃ or CH═COCH₃,

[0035] at least one of R₁ to R₄ is an aromatic ring, a substitutedaromatic ring, a heterocycle or a substituted heterocycle (provided thatwhen both R₆ and R₇ are hydroxyl groups, any one of R₁ to R₄ is not aphenyl group); or

[0036] at least one of R₁ to R₄ is SW₈ (wherein W₈ is a lower alkylgroup or a substituted lower alkyl group) or S(O)W₉ (wherein W₉ is alower alkyl group or a substituted lower alkyl group) (provided that R₇is a hydrogen atom when Z is O); or

[0037] R₂ is either a lower alkyl group or a substituted lower alkylgroup and, at the same time, R₈ is a hydroxyl group (provided that thenumber of carbon atoms of the lower alkyl group is 3 or more when Z isO); or

[0038] at least one of R₁ to R₄ is a lower alkylcarbonyl group (providedthat the number of carbon atoms of the lower alkyl group is 3 or more),a cycloalkylcarbonyl group or a cycloalkenylcarbonyl group and, at thesame time, R₈ is a hydroxyl group; or

[0039] at least one of R₁ to R₄ is a cyano group; or

[0040] at least one of R₁ to R₄ is a halogen and, at the same time, Z isany one of S, S═O and SO₂; or

[0041] R₅ and R₆ are hydroxyl groups and, at the same time, Z is S; or

[0042] at least one of R₁ to R₄ is —C(═NOR)CH₃ (wherein R is a hydrogenatom or a lower alkyl group), an optical isomer thereof, a conjugatethereof or a pharmaceutically acceptable salt thereof.

[0043] (2) The compound stated in the above (1), wherein R₆ is ahydroxyl group.

[0044] (3) The compound stated in the above (1), wherein R₆ and R₇ arehydroxyl groups.

[0045] (4) The compound stated in the above (1), wherein R₆ and R₈ arehydroxyl groups.

[0046] (5) The compound stated in the above (1), wherein R₅ and R₆ arehydroxyl groups.

[0047] (6) The compound stated in any one of the above (1) to (5),wherein the X—Y bond is a single bond and X is CW₁W₂ (wherein at leastone of W, and W₂ is any one selected from a lower alkyl group, asubstituted lower alkyl group, a cycloalkyl group and a cycloalkenylgroup) or the X—Y bond is a double bond and X is CW₃ (wherein W₃ is anyone selected a lower alkyl group, a substituted lower alkyl group, acycloalkyl group and a cycloalkenyl group).

[0048] (7) The compound stated in any one of the above (1) to (6),wherein Y is CO.

[0049] (8) The compound stated in the above (6), wherein the lower alkylgroup is any one of a methyl group, an ethyl group, a n-propyl group, anisopropyl group, n-butyl group, a sec-butyl group, an isobutyl group anda tert-butyl group.

[0050] (9) The compound stated in any one of the above (1) to (5),wherein R₂ or R₃ is any one of a heterocycle, a substituted heterocycle,an aromatic ring and a substituted aromatic ring.

[0051] (10) The compound according to any one of the above (1) to (5),wherein the heterocyle is an aromatic heterocyle.

[0052] (11) The compound according to any one of the above (1) to (5),wherein R₂ or R₃ is SW₈ (wherein W₈ is a lower alkyl group or asubstituted lower alkyl group) or S(O)W₉ (wherein W₉ is a lower alkylgroup or a substituted alkyl group).

[0053] (12) The compound stated in the above (11), wherein the loweralkyl group is any one of a methyl group, an ethyl group, a n-propylgroup, an isopropyl group, an n-butyl group, a sec-butyl group, anisobutyl group and a tert-butyl group.

[0054] (13) The compound stated in any one of the above (1) to (12),wherein Z is S.

[0055] (14) The compound stated in the above (1) which is7,8-dihydroxy-11-ethyl-10,11-dihydrodibenzo[b,f]thiepin-10-one.

[0056] (15) The compound stated in the above (1) which is11-diethyl-7,8-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one.

[0057] (16) The compound stated in the above (1) which is7,9-dihydroxy-2-methylthio-10,11-dihydrodibenzo[b,f]thiepin-10-one.

[0058] (17) A method of preparing a compound represented by formula (1),

[0059] wherein

[0060] when the X—Y bond is a single bond, X and Y, which may be thesame or different, are each independently any one selected from thegroup consisting of CW₁W₂ (wherein W₁ and W₂, which may be the same ordifferent, are each independently any one of a hydrogen atom, a halogen,a hydroxyl group, a lower alkyl group, a substituted lower alkyl group,a lower alkoxy group, a cycloalkyl group and a cycloalkenyl group), C═O,and C═NOW₃ (wherein W₃ is a hydrogen atom or a lower alkyl group);

[0061] when the X—Y bond is a double bond, X and Y, which may be thesame or different, are each independently CW₄ (wherein W₄ is any one ofa hydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, asubstituted lower alkyl group, a lower alkoxy group and an acyloxygroup);

[0062] Z is any one selected from O, S, S═O and SO₂;

[0063] U is C or N;

[0064] R₁ to R₄, which may be the same or different, are eachindependently any one selected from the group consisting of a hydrogenatom, a lower alkyl group, a substituted lower alkyl group, a cycloalkylgroup, a substituted cycloalkyl group, a lower alkenyl group, asubstituted lower alkenyl group, a lower alkynyl group, a substitutedlower alkynyl group, a halogen, a lower alkylcarbonyl group, asubstituted lower alkylcarbonyl group, a trihalomethyl group, V₁W₅(wherein V₁ is any one of O, S, S═O and SO₂; and W₅ is any one of ahydrogen atom, a lower alkyl group, a substituted lower alkyl group, alower alkylcarbonyl group and a substituted lower alkylcarbonyl group,an acyloxy group and a trihalomethyl group), a nitro group, an aminogroup, a substituted amino group, a cyano group, an acyl group, anacylamino group, a substituted acyl group, a substituted acylaminogroup, an aromatic ring, a substituted aromatic ring, a heterocycle anda substituted heterocycle (when U is N, R₄ does not exist in somecases);

[0065] R₅ to R₈, which may be the same or different, are eachindependently any one selected from the group consisting of a hydrogenatom, a lower alkyl group, a substituted lower alkyl group, a loweralkenyl group, a substituted lower alkenyl group, a lower alkynyl group,a substituted lower alkynyl group, a halogen, a lower alkylcarbonylgroup, a substituted lower alkylcarbonyl group, a trihalomethyl group,V₂W₇ (wherein V₂ is any one selected from O, S, S═O and SO₂; and W₇ isany one selected from a hydrogen atom, a lower alkyl group, asubstituted lower alkyl group, a lower alkylcarbonyl group, asubstituted lower alkylcarbonyl group and a trihalomethyl group), anitro group, an amino group, a substituted amino group, an acylaminogroup, an aromatic ring, a substituted aromatic ring, a heterocycle anda substituted heterocycle;

[0066] provided that at least one of R₅ to R₈ is a hydroxyl group[provided that at least one of R₅, R₇ or R₈ is a hydroxy group when theX—Y bond is CH(C₂H₅)CO and R₆ is a hydroxyl group] when X is CHW₀, CW₀W₀or CW₀ (wherein W₀ is any one selected from a lower alkyl group and asubstituted lower alkyl group) and at least one of R₅ to R₈ is ahydroxyl group and, at the same time, at least one of the other R₅ to R₈is a group of OR (wherein R is any one selected from the groupconsisting of a hydrogen atom, a lower alkyl group, a substituted loweralkyl group, a lower alkylcarbonyl group and a substituted loweralkylsilyl group) when X is other than CHW₀, CW₀W₀ or CW₀ (wherein W₀ isany one selected from a lower alkyl group and a substituted lower alkylgroup);

[0067] in addition, when the X-Y is CH₂CH₂, CHBrCH₂, CH₂CO, CHBrCO,CH═CH, CH═COCOCH₃ or CH═COCH₃,

[0068] at least one of R₁ to R₄ is an aromatic ring, a substitutedaromatic ring, a heterocycle or a substituted heterocycle (provided thatwhen both R₆ and R₇ are hydroxyl groups, any one of R₁ to R₄ is not aphenyl group); or

[0069] at least one of R₁ to R₄ is SW₈ (wherein W₈ is a lower alkylgroup or a substituted lower alkyl group) or S(O)W₉ (wherein W₉ is alower alkyl group or a substituted lower alkyl group) (provided that R₇is a hydrogen atom when Z is O); or

[0070] R₂ is either a lower alkyl group or a substituted lower alkylgroup and, at the same time, R₈ is a hydroxyl group (provided that thenumber of carbon atoms of the lower alkyl group is 3 or more when Z isO); or

[0071] at least one of R₁ to R₄ is a lower alkylcarbonyl group (providedthat the number of carbon atoms of the lower alkyl group is 3 or more),a cycloalkylcarbonyl group or a cycloalkenylcarbonyl group and, at thesame time, R₈ is a hydroxyl group; or

[0072] at least one of R₁ to R₄ is a cyano group; or

[0073] at least one of R₁ to R₄ is a halogen and, at the same time, Z isany one of S, S═O and SO₂; or

[0074] R₅ and R₆ are hydroxyl groups and, at the same time, Z is S; or

[0075] at least one of R₁ to R₄ is —C(═NOR)CH₃ (wherein R is a hydrogenatom or a lower alkyl group),

[0076] an optical isomer thereof, a conjugate thereof or apharmaceutically acceptable salt thereof,

[0077] which comprises, in any order, the reaction steps of {circle over(1)} bonding a ring A to a ring C by the Ullmann reaction as shown informula 2 and {circle over (2)} bonding a ring A to a ring C by theFriedel-Crafts reaction or photoreation as shown in formula 3,

[0078] wherein

[0079] Q, S and W are each any substitutent;

[0080] U is C or N;

[0081] one of X and Y is a leaving group and the other is a nucleophilicgroup; and

[0082] Z is any one of O, S, SO and SO₂.

[0083] (18) The method stated in the above (17) further comprising atleast one step of the step of carbon atom increasing reaction, the stepof conversion reaction of a substituent, the step of introductionreaction of a substituent, the step of removal of the protection of asubstituent, the step of forming a salt and the step of performingoptical resolution. The order of these steps and stepl and step2 of (17)is not limited. A person skilled in the art can decide the orderconsidering a structure of the target compound and other conditions.

[0084] (19) A pharmaceutical composition comprising an effective amountof the compound stated in any one of the above (1) to (16) and apharmaceutically acceptable carrier or diluent.

[0085] (20) The pharmaceutical composition stated in the above (19)which utilizes the tracheal smooth muscles relaxing action of thecompound.

[0086] (21) The pharmaceutical composition stated in the above (19)which utilizes the inhibitory effect on airway hypersensitivity of thecompound.

[0087] (22) The pharmaceutical composition stated in the above (19)which utilizes the inhibitory effect on inflammatory cells filtration ofthe compound.

[0088] (23) The pharmaceutical composition stated in the above (19)which is used as the antiasthmatic drug.

[0089] (24) A compound of the following formula,

[0090] wherein Q is a lower alkyl group, an optical isomer thereof or asalt thereof.

[0091] (25) A compound of the following formula,

[0092] wherein

[0093] Q is a lower alkyl group; and

[0094] Q₁ to Q₅ which may be the same or different are eachindependently any one selected from a hydrogen atom, a lower alkoxygroup and a hydroxyl group, an optical isomer thereof or a salt thereof.

[0095] Further, when the compounds and their salts described in theabove (1) contain an asymmetric carbon atom in the structure, theoptical active compounds and the racemic compounds are also included inthe scope of the present invention. In addition, the compounds and theirsalts described in the above (1) may be either the hydrates ornonhydrates and may be the solvates.

BRIEF DESCRIPTION OF THE DRAWINGS

[0096]FIG. 1 is a graph showing the inhibitory effects of the compoundsof the present invention on the immediate and late asthmatic responsesin actively sensitized guinea pigs.

[0097]FIG. 2 is a graph showing the inhibitory effects of the compoundsof the present invention on the immediate and late asthmatic responsesin actively sensitized guinea pigs.

[0098]FIG. 3 is a graph showing the inhibitory effects of the compoundsof the present invention on the number of inflammatory cells in thebronchoalveolar lavage fluid 24 hours after challenge with an antigen inactively sensitized guinea pigs.

[0099]FIG. 4 is a graph showing the inhibitory effects of the compoundof the present invention on the airway reactivity to acetylcholine 22 to26 hours after challenge with an antigen in actively sensitized guineapigs.

BEST MODE FOR CARRYING OUT THE INVENTION

[0100] The term “halogen” as used in the specification of the presentapplication refers to any atom of fluorine, chlorine, bromine andiodine. Further, the term “trihalomethyl group” as used herein refers toa group in which three hydrogen atoms are substituted with halogenatoms, and these three halogen atoms may be all the same or may beconstituted of two or more different halogen atoms.

[0101] The term “lower alkyl group” as used herein refers to, forexample, a straight-chain or branched chain C₁l₆ alkyl group, and theC₁₋₆ alkyl group includes, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. As thesubstituent which the “lower alkyl group” may have, one or more selectedfrom, for example, hydroxyl, amino, carboxyl, nitro, an aryl group, asubstituted aryl group, a mono- or di-lower alkylamino group (including,for example, mono- or di-C₁₋₆ alkylamino such as methylamino,ethylamino, propylamino, dimethylamino and diethylamino), lower alkoxy(including, for example, C₁₋₆ alkoxy such as methoxy, ethoxy, propoxyand hexyloxy), lower alkylcarbonyloxy (including, for example, C₁₋₆alkylcarbonyloxy such as acetoxy and ethylcarbonyloxy) and a halogenatom are employed. Further, the lower alkyl moiety in the “lower alkoxygroup” as used herein refers to the above described “lower alkyl group”.

[0102] The term “cycloalkyl group” as used herein refers to, forexample, a C₃₋₈ cyclic alkyl group. The C₃₋₈ cycloalkyl group includes,for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcyclooctyl. As the substituent which the “cycloalkyl group” may have,one or more selected from, for example, hydroxyl, amino, carboxyl,nitro, a mono- or di-lower alkylamino group (including, for example,mono- or di-C₁₋₆ alkylamino such as methylamino, ethylamino,propylamino, dimethylamino and diethylamino), a lower alkoxy (including,for example, C₁₋₆ alkoxy such as methoxy, ethoxy, propoxy and hexyloxy),a lower alkylcarbonyloxy (including, for example, alkylcarbonyloxy suchas acetoxy and ethylcarbonyloxy) and a halogen atom are employed.

[0103] The term “cycloalkenyl group” as used herein refers to acycloalkenyl group having one or more double bonds on the ring moiety.

[0104] The term “lower alkenyl group” as used herein refers to, forexample, a straight chain or branched chain C₂₋₆ alkenyl group. The C₂₋₆alkenyl group includes, for example, vinyl, allyl, 2-methylallyl,isopropenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl and3-hexenyl. As the substituent which the “lower alkenyl group” may have,one or more selected from, for example, hydroxyl, amino, carboxyl,nitro, mono- or di-lower alkylamino group (including, for example, mono-or di-C₁₋₆ alkylamino such as methylamino, ethylamino, propylamino,dimethylamino and diethylamino), lower alkoxy such as methoxy, ethoxy,propoxy and hexyloxy), lower alkylcarbonyloxy (including, for example,C₁₋₆ alkylcarbonyloxy such as acetoxy and ethylcarbonyloxy) and ahalogen atom are employed.

[0105] The term “lower alkynyl group” as used herein refers to, forexample, a straight chain or branched chain C₂I₆ alkynyl group. The C₂₋₆alkynyl group includes, for example, ethynyl, 2-propynyl, 2-butynyl,3-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl and 3-hexynyl. As thesubstituent which the “lower alkynyl group” may have, one or moreselected from, for example, hydroxyl, amino, carboxyl, nitro, mono- ordi-lower alkylamino (including, for example, a mono- or di-C₁₋₆alkylamino such as methylamino, ethylamino, propylamino, dimethylaminoand diethylamino), lower alkoxy (including, for example, C₁₋₆ alkoxysuch as methoxy, ethoxy, propoxy and hexyloxy), lower alkylcarbonyloxy(including, for example, C₁₋₆ alkylcarbonyloxy such as acetoxy andethylcarbonyloxy) and a halogen atom are employed.

[0106] The lower alkyl moiety in the “lower alkylcarbonyl group” as usedherein refers to the above described “lower alkyl group”.

[0107] As the substituent in the term “substituted amino group” as usedherein, one or more selected from, for example, hydroxyl, carboxyl,nitro, mono- or di-lower alkyl (including, for example, mono- or di-C₁₋₆alkyl such as methyl, ethyl, n-propyl, isopropyl, dimethyl and diethyl),lower alkoxy (including, for example, C₁₋₆ alkoxy such as methoxy,ethoxy, propoxy and hexyloxy), lower alkylcarbonyloxy (including, forexample, C₁₋₆ alkylcarbonyloxy such as acetoxy and ethylcarbonyloxy) anda halogen atom are employed.

[0108] The term “acyl group” as used herein refers to —COR wherein R isany one of a hydrogen atom, a lower alkyl group, a lower alkenyl group,a lower alkynyl group, a C₃₋₈ cycloalkyl group and a monocyclic orpolycyclic aromatic ring or a hereocycle. The acyl moiety in the terms“acyloxy group” and “acylamino group” as used herein refers to the abovedescribed acyl group. The substituent which the “acyl group” and the“acylamino group” may have refers to a substituent on the carbon atom ofR, and one or more selected from, for example, hydroxyl, amino,carboxyl, nitro, mono- or di-lower alkylamino (including, for example, amono- or di-C₁₋₆ alkylamino such as methylamino, ethylamino,propylamino, dimethylamino and diethylamino), lower alkoxy (including,for example, C₁₋₆ alkoxy such as: methoxy, ethoxy, propoxy andhexyloxy), lower alkylcarbonyloxy (including, for example, C₁₋₆alkylcarbonyloxy such as acetoxy and ethylcarbonyloxy) and a halogenatom are employed.

[0109] The term “aromatic ring” as used herein refers to a group ofatoms remaining after removal of one hydrogen atom from an aromatichydrocarbon, that is, an aryl group. Particularly, C₆₋₁₄ alkyl groupsare preferred. Such C₆₋₁₄ alkyl groups that can be used include, forexample, phenyl, naphthyl, tolyl, xylyl, biphenyl, 1-naphthyl,2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl,2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenathryl, 1-azulenyl,2-azulenyl, 4-azulenyl, 5-azulenyl and 6-azulenyl. As the substituentwhich the “aromatic ring” may have, one or more selected from, forexample, lower alkyl, hydroxyl, amino, carboxyl, nitro, mono- ordi-lower alkylamino (including, for example, a mono- or di-C₁₋₆alkylamino such as methylamino, ethylamino, propylamino, dimethylaminoand diethylamino), lower alkoxy (including, for example, C₁₋₆ alkoxysuch as methoxy, ethoxy, propoxy and hexyloxy), lower alkylcarbonyloxy(including, for example, C₁₋₆ alkylcarbonyloxy such as acetoxy andethylcarbonyloxy), trihalomethane, trihalomethoxy, a halogen atom andaryl such as phenyl are used.

[0110] The term “heterocycle” as used herein refers to a group of atomsremaining after removal of one hydrogen atom from a 3- to 7-memberedheterocycle which contains one to four hetero atoms selected from, forexample, a nitrogen atom, an oxygen atom, and a sulfur atom in additionto carbon atoms. The heterocycle may be condensed. Exemplaryheterocycles include, for example, oxetane, tetrahydrofuran,tetrahydrothiophene, tetrahydropyran, pyrrole, azetidine, pyrrolidine,piperidine, piperazine, homopiperidine, morpholine, furan, pyridine,benzofuran and benzothiophene. As the substituent which the“heterocycle” may have, one or more selected from, for example,hydroxyl, amino, carboxyl, nitro, mono- or di-lower alkylamino(including, for example, a mono- or di-C₁₋₆ alkylamino such asmethylamino, ethylamino, propylamino, dimethylamino and diethylamino),lower alkoxy (including, for example, C₁₋₆ alkoxy such as methoxy,ethoxy, propoxy and hexyloxy), lower alkylcarbonyloxy (including, forexample, C₁₋₆ alkylcarbonyloxy such as acetoxy and ethylcarbonyloxy) anda halogen atom are used.

[0111] Further, examples of particularly preferred compounds in thepresent invention include the following compounds, their opticalisomers, conjugated compounds and salts.

[0112] (1) Compounds in which two hydroxyl groups are present on ringC(R₅ to R₈) and a lower alkyl group is present in the 11-position(X-position). Specifically,7,8-dihydroxy-11-ethyl-10,11-dihydrodibenzo[b,f]thiepin-10-one,11-diethyl-7,8-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one,11-methyl-7,8-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one and thelike can be illustrated.

[0113] (2) Compounds in which two hydroxyl groups are present on ring C(R₅ to R₈) and a thio-lower alkyl group is present on ring A (R₁ to R₄).Specifically,7,9-dihydroxy-2-methylthio-10,11-dihydrodibenzo[b,f]thiepin-10-one,8-methylthio-10,11-dihydrodibenzo[b,f]thiepin-1,3-diol and the like canbe illustrated.

[0114] (3) Compounds in which two hydroxyl groups are present on ring C(R₅ to R₈) and a heterocycle is bonded to ring A (R₁ to R₄).Specifically,7,9-dihydroxy-3-(2-furyl)-10,11-dihydrodibenzo[b,f]thiepin-10-one,7-(2-thienyl)-10,11-dihydrodibenzo[b,f]thiepin-1,3-diol,7-(2-furyl)-10,11-dihydrodibenzo[b,f]thiepin-1,3-diol and the like canbe illustrated.

[0115] As the salts of the compounds of the present invention, acidaddition salts whose acids are pharmaceutically or physiologicallyacceptable ones are preferably employed. Such salts which can be usedinclude, for example, salts with inorganic acids (such as hydrochloricacid, phosphoric acid, hydrobromic acid and sulfuric acid); organicacids(such as acetic acid, formic acid, propionic acid, fumaric acid,maleic acid, succinic acid, tartaric acid, lactic acid, citric acid,malic acid, oxalic acid, benzoic acid, methanesulfonic acid,p-toluenesulfonic acid and benzenesulfonic acid); and alkalis (such assodium, potassium, magnesium, calcium, ammonium, pyridine andtriethylamine).

[0116] The conjugates of the compounds of the present invention include,for examples, glucuronic acid conjugates and sulfuric acid conjugates ofthe compounds represented by formula (1), their optical isomers andtheir salts.

[0117] Next, the method for the preparation of the compounds of thepresent invention or their salts will be described.

[0118] The tricyclic condensed heterocyclic compound of the presentinvention is a 6-7-6-membered tricyclic compounds consisting of threerings of A, B and C as shown in formula (4) below.

[0119] The skeleton of this compound can be prepared by the combinationof bonding of ring A to ring C by the Ullmann reaction and bonding ofring A to ring C by the Friedel-Crafts reaction or photoreaction.Depending on the starting material and the target compound, it isnecessary to add a carbon atom increasing reaction. Furthermore, ifnecessary or desired, the target compound can be obtained by carryingout a substituent introduction reaction and a substituent conversionreaction.

[0120] For example, the first step is to bond ring A to ring C by theUllmann reaction. Then, the second step (carbon atom increasingreaction) is to increase W of carbon atoms to make ring B 7-membered.Furthermore, the third step is to form ring B by the Friedel-Craftsreaction. The fourth step (substituent introduction reaction) is tointroduce a necessary substituent such as a halogen and a lower alkylgroup into the tricyclic compound thus formed.

[0121] As regards the introduction of a substituent, it is possible tointroduce the substituent either into the starting material of the firststep or in the middle of the carbon atom increasing reaction of thesecond step and thus, the introduction of the substituent can beselected by taking the type of the target compound or the like intoconsideration when the occasion demands. Furthermore, if necessary ordesired, the carbonyl group of the 10-position can be reduced or thesubstituent, OR (for example; OCH₃), can be converted into OH by thereaction of removing the protection.

[0122] Now the reaction scheme of each step will be illustrated.

[0123] {circle over (1)} Ullmann Reaction

[0124] wherein

[0125] one of X and Y is a leaving group; and the other is anucleophilic agent.

[0126] {circle over (2)}-1 Friedel-Crafts Reaction

[0127] {circle over (2)}-2 Photoreaction

[0128] {circle over (3)} Carbon Atom Increasing Reaction

[0129] {circle over (4)} Conversion Reaction of Halogen to AnotherFunctional Group

[0130] {circle over (5)} Introduction Reaction of Alkyl Group orAlkylcarbonyl Group

[0131] {circle over (6)} Conversion Reaction at 10-Position

[0132] {circle over (7)} Reaction of Deprotection

[0133] The above mentioned reaction scheme of each step will beexplained as follows.

[0134] {circle over (1)} Ullmann Reaction

[0135] Ring A having a necessary substituent and a substituted benzenecorresponding to ring C are formed into a coupled compound by theUllmann reaction. The leaving group in the Ullmann reaction which can beused includes, for example, a halogen (for example, chlorine, bromine oriodine), C₆₋₁₀ arylsulfonyloxy (for example, benzenesulfonyloxy orp-toluenesulfonyloxy) and C₁₋₄ alkylsulfonyloxy (for example,methanesulfonyloxy) and above all, a halogen (for example, chlorine,bromine or iodine) is preferred. The nucleophilic side which can be usedincludes, for example, a precursor having a functional group containingoxygen or sulfur and above all, a substituted phenol, a substitutedthiophenol and a substituted disulfide are preferred.

[0136] {circle over (2)} Friedel-Crafts Reaction or Photoreaction

[0137] The reaction of further bonding ring A to ring C can use a methodwhich is conventionally carried out as the Friedel-Crafts reaction. Forexample, the methods of “Comprehensive Organic Synthesis: TheIntramolecular Aromatic Friedel-Crafts Reaction”, Vol. 2, pp753 (1991),J. Org. Chem., 52, 849 (1987) and Synthesis, 1257 (1995) or the onescorresponding thereto can be used. Further, by using thephotocyclization method as shown in Japanese Patent Publication (Kokai)No. Hei 10-204079/1998) or the one corresponding thereto, a substitutedacetophenone compound can be directly led to a cyclized compound.Further, the order of the Ullmann reaction and these reactions can alsobe changed.

[0138] {circle over (3)} Carbon Atom-increasing Reaction

[0139] When a substituted phenyl acetate derivative is used in theUllmann reaction, it can be directly led to a cyclized compound but whena substituted benzoic acid derivative is used, the moiety correspondingto ring B is subjected to a carbon atom-increasing reaction. In thisinstance, a substituted benzoic acid derivative can be led to thesubstituted phenyl acetate via the substituted benzyl alcohol compound,the substituted benzyl halide compound and the substituted benzylnitrile compound. Further, the substituted benzyl halide compound canalso be directly led to the substituted phenyl acetate with carbondioxide. By the Willgerodt reaction, the substituted acetophenonecompound is formed into the substituted morpholine compound which can bethen led to the substituted phenyl acetate.

[0140] {circle over (4)} Conversion Reaction of Halogen to AnotherFunctional Group

[0141] The introduction reaction of a heterocycle, a substituted phenylring or a lower alkyl group can be carried with palladium by using themethods of Chem. Rev., 95, 2457 and “Organic Reactions”, Vol. 50 (1997)or one corresponding thereto.

[0142] {circle over (5)} Reaction of Introduction of Alkyl Group orAlkylcarbonyl Group

[0143] The introduction of an alkyl group such as an ethyl group can becarried out in the presence of a base for the cyclized compound in ananhydrous solvent in the presence of an alkyl halogenating agent or analkali with the use of a phase transfer catalyst and an alkylhalogenating agent. Further, the alkyl group can be introduced intoeither an intermediate of the carbon atom increasing reaction beforecyclization or the starting material before the Ullmann reaction. Theintroduction of an alkylcarbonyl group can be carried out by using theFriedel-Crafts reaction.

[0144] {circle over (6)} Conversion Reaction at 10-Position

[0145] The carbonyl group of the cyclized compound is reduced to analcohol compound of the cyclized compound which is then formed into theolefinic compound by dehydration reaction, and this oleinic compound canbe led to the decarbonylated compound by catalytic reduction. Further,the alcohol compound of the cyclized compound is subjected to thereaction {circle over (7)} of Deprotection to form the olefinic compoundwhich can be then led to the decarbonylated compound by reduction.Alternatively, the cyclized compound can be directly led to thedecarbonylated compound by Wolff-Kishner reduction.

[0146] {circle over (7)} Reaction of Deprotection

[0147] The reaction of deprotection can be carried out with a pyridinesalt or a boron halide.

[0148] The preparation of the compounds of the present invention ispreferably carried out in a solvent, and such a solvent that can be usedinclude, for example, aromatic hydrocarbons such as benzene, toluene andxylene; ethers such as diethyl ether, tetrahydrofuran and dioxane;amides such as dimethylformamide and dimethylacetamide; sulfoxide suchas dimethyl sulfoxide; nitrites such as acetonitrile;N-methyl-2-pyrrolidone and anhydrous solvents thereof. The reactiontemperature is −78° C. to 200° C., and the reaction time is 30 minutesto several days, and the reaction is advantageously carried out under astream of nitrogen or argon. The reaction product can be isolated andpurified by known means such as solvent extraction, acidity oralkalinity conversion, transdissolution, salting out, crystallization,recrystallization and chromatography.

[0149] In the method of the present invention, when the substituent isan amino group, the amino group is preferably protected, and aprotective group which is commonly used in the field of peptidechemistry and the like can be used, and a protective group of the typewhich forms an amide, such as formyl, acetyl and benzoyl; a protectivegroup of the type which forms a carbamate, such as tert-butoxycarbonyland benzyloxycarbonyl; a protective group of the imino type such asdimethylaminomethylene, benzylidene, p-methoxybenzylidene anddiphenylmethylene are preferably used. Preferred protective groups whichcan be used are, for example, formyl, acetyl and dimethylaminomethylene.Further, when the product obtained in the above described reactions hasa protective group, the protective group can be removed by theconventional method. For example, the protective group can be removed byhydrolysis with an acid or a base or by procedure of deprotection suchas catalytic reduction or the like.

[0150] Further, when the compound of the present invention has anasymmetric carbon, an optical isomer can be obtained by usingconventionally known various optically resolving methods such as anoptical isomer resolving column.

[0151] In addition, the compounds of the present invention or theirpharmaceutically or physiologically acceptable salts thereof have a widerange of pharmacological actions such as the excellent relaxing actionof tracheal smooth muscles, the inhibition of airway hypersensitivityand the inhibition of infiltration of inflammatory cells into the airwayand can be used as safe antiasthmatic drugs and the like for mammals(humans, mice, dogs, rats, cattle and the like). Specifically, when theyare used as antiasthmatic drugs for humans, the dose may vary dependingon the age, weight, symptom of disease, route of administration,frequency of administration and the like, and they are administered witha dose of 0.1 to 100 mg/kg daily, preferably 1 to 50 mg/kg daily once ordividedly twice. The route of administration may be either oral orparenteral.

[0152] The compounds of the present invention or their salts may beadministered as the bulk drug but they are usually administered in theform of preparations with a drug carrier. As concrete examples, tablets,capsules, granules, fine granules, powders, syrups, injections,inhalants and the like are employed. These pharmaceutical preparationscan be prepared according to conventional techniques. As carriers oforal preparations, the substance which is conventionally employed in thefield of pharmaceutical preparation, such as starch, mannitol,crystalline cellulose and sodium carboxymethyl cellulose can be used. Ascarriers for injections, distilled water, a physiological saline,glucose solution, a transfusion and the like can be used. Otheradditives which are commonly employed in pharmaceutical preparations cansuitably be added.

REFERENTIAL EXAMPLES

[0153] Examples of the method for preparing the starting materialsubstances of the present invention and each of the above describedreactions will be explained below but the present invention is notlimited to them and may be changed without departing from the scope ofthe present invention. The elution in the chromatography of ReferentialExample was carried out under observation by thin-layer chromatography(TLC) unless expressly stated. In the TLC observation, “60F₂₅₄” of Merckwas used as the TLC plate and as the developing solvent, a solvent whichwas used as the eluting solvent in column chromatography was used.Further, an UV detector was employed in detection. As the silica gel forthe column chromatography, “Silica Gel 60” (70 to 230 mesh) of Merck or“Microsphere Gel D75-60A” of Asahi Glass was used. The term “roomtemperature” means from about 10° C. to about 35° C.

Referential Example 1

[0154] Method of Preparing 4-Bromo-2-chlorobenzoic Acid (3)

[0155] Synthesis of 4-Amino-2-chlorobenzoic Acid (2)

[0156] In ethanol (250 mL) was dissolved 100 g (F.W. 201.57, 496 mmol)of 2-chloro-4-nitrobenzoic acid (1) and after replacing with argon, a10% palladium carbon catalyst (4.0+1.5 g) was added thereto. Afterreplacing with hydrogen, the mixture was stirred at room temperature for72 hours. The formed crystal was dissolved with acetone and filtered toremove the catalyst. The solvent was distilled under reduced pressure toquantitatively obtain 88 g of the target 4-amino-2-chlorobenzoic acid(2).

[0157] Melting point: 215-217° C.

[0158] Synthesis of 4-Bromo-2-chlorobenzoic Acid (3)

[0159] Eighty-eight grams (F.W. 171.58, 513 mmol) of4-amino-2-chlorobenzoic acid (2), 48% hydrobromic acid (304 mL) andwater (304 mL) were heated at 120° C. for one hour and dissolved to forma hydrobromate salt. Under stirring, the solution was cooled (ice-sodiumchloride), and an aqueous solution (water, 250 mL) of 44.4 g (F.W.69.00, 643 mmol) of sodium nitrite was added thereto while maintaining5° C. or below.

[0160] In a beaker 120.8 g (F.W. 80.79, 2.83 mmol) of copper bromide in48% hydrobromic acid (331 mL) was made 0° C. and the prepared diazoniumsalt solution was slowly added thereto with stirring so as not to foam.After completion of the addition, the resulting solution was heated in ahot water bath until the generation of nitrogen ceased. The reactionsolution was cooled by standing and then, extracted with ethyl acetate.The extract was treated according to the conventional method to obtain88.3 g (73%) of a desired 4-bromo-2-chlorobenzoic acid (3).

[0161] Melting Point: 152-160° C.

[0162] IR (KBr)ν_(max) cm⁻¹: 3090, 1682, 1578

[0163]¹H NMR (400 MHz, CDCl₃) δ: 7.50 (1H, dd, J=8.5, 2.0 Hz, Ar—H),7.69 (1H, J=2 Hz, Ar—H), 7.89 (1H, J=8.5 Hz, Ar—H)

Referential Example 2

[0164] Method of Preparing of Di-(3,5-dimethoxyphenyl)disulfide (9)

[0165] To a suspension of 25.0 g (F.W. 153.18, 163.2 mmol) of3,5-dimethoxyaniline (4) in 500 mL of water was added 40.8 mL (489.6mmol) of concentrated hydrochloric acid to completely dissolve thehydrochloride by stirring and heating. To the resulting solution wasadded 400 mL of water and then, ice-cooled. While maintaining thereaction temperature (inner temperature) at 5° C. or below andvigorously stirring, a solution of 11.8 g (F.W. 69.00, 171.4 mmol) ofsodium nitride in 40 mL of water was carefully added to the resultingsolution. The obtained solution was stirred at the same temperature forabout 30 minutes to prepare a dizaonium salt solution.

[0166] A suspension of 680.5 g (F.W. 160.30, 4243.2 mol) of potassiumxanthogenate (6) in 550 mL of water was completely dissolved by raisingthe temperature to 65 to 70° C. to prepare a potassium xanthogenatesolution.

[0167] To this solution maintained at 65 to 70° C. was slowly addeddropwise the dizaonium salt solution maintained at 5° C. of below over30 minutes. This procedure was repeated four times.

[0168] The resulting solution was stirred at 65 to 70° C. for about onehour and then, cooled to room temperature by standing. The resultingsolution was extracted with ethyl acetate three times. The extract waswashed with 1N sodium hydroxide, water and a saturated sodium chlorideaqueous solution in the order named. After drying with anhydrous sodiumsulfate, the solvent was removed under reduced pressure to obtain acrude product (7). By column chromatography (developing solvent;hexane:ethyl acetate=7:1) 122.31 g of product (7)[and a mixture withcompound (9)] was obtained.

[0169] In 450 mL of ethanol was dissolved 85.7 g of product (7)[and amixture with compound (9)] and then, 50 mL of water and 200.0 g (F.W.56.11, 4986.0 mmol) of potassium hydroxide were added thereto. Thereaction solution was stirred under refluxing for 10 minutes. Afterhaving confirmed the absence of compound (7) by TLC, the reactionsolution was cooled by standing and neutralized with 3N hydrochloricacid. Under reduced pressure, ethanol was distilled off and then, theresidue was extracted with ethyl acetate three times and the extract waswashed with a saturated sodium chloride aqueous solution. To the organiclayer was added 25.0 g (F.W. 79.54, 314.3 mmol) of copper (II) oxide(powder) and stirred at room temperature while bubbling air (or oxygen)thereinto until thiol (8) disappeared. After removing insolubles byfiltration, water was added to the solution thus obtained and theresulting solution was extracted with ethyl acetate three times and theextract was washed with 1N hydrochloric acid, water and a saturatedsodium chloride aqueous solution in the order named. After drying withanhydrous sodium sulfate, the solvent was removed under reduced pressureto obtain 53.65 g of a crude product (9). This crude product (9) waspurified by column chromatography (developing solvent; hexane:ethylacetate=19:1) to obtain 34.87 g (pure) (F.W.338.44, 103.0 mmol) and11.05 g (crude) of disulfide (9) in 41t yield.

[0170] Melting Point: 152-160° C.

[0171] IR (KBr)ν_(max) cm⁻¹: 3090, 1682, 1578

[0172]¹H NMR (400 MHz, CDCl₃) δ: 7.50 (1H, dd, J=8.5, 2 Hz, Ar—H), 7.69(1H, J=2 Hz, Ar—H), 7.89 (1H, J=8.5 Hz, Ar—H)

Referential Example 3

[0173] Method of Preparing of Di-(3,4-dimethoxyphenyl)disulfide

[0174] To 100 g of veratrole (10) was added 500 mL of anhydrousmethylene chloride and stirred at 0° C. To this solution was added 235mL of chlorosulfonic acid over one hour and stirred at 50° C. for 30minutes. The resulting solution was added dropwise to 1.5 L of methanolat 0° C. over 40 minutes and then, 290 mL of hydrochloric acid and 570 gof stannous chloride were added thereto at room temperature and stirredfor two hours. The obtained solution was concentrated under reducedpressure to half the volume and then, the resulting solution wasextracted with toluene and the organic layer was washed with 12%hydrochloric acid, water and a saturated sodium chloride solution in theorder named, and subsequently dried with anhydrous magnesium sulfate andthe solvent was distilled off under reduced pressure. The residue wasdissolved in ethyl acetate and then, 20 g of cupric oxide was addedthereto and stirred while bubbling air. The catalyst was filtered andthe filtrate was washed with ethyl acetate and then, recrystallized fromethyl acetate-hexane to obtain a desired compound (11). (Total yield21%)

[0175] EM-MS: 338 (M+), 169 (Base)

[0176] NMR (CDCl₃): 3.83 (6H, s), 3.87 (6H, s), 6.79 (2H, d, J=8.3 Hz),7.01 (2H, d, J=2.1 Hz), 7.05 (2H, dd, J=2.1, 8.3 Hz)

Referential Example 4

[0177] Method of Preparing8-Bromo-10,11-dihydrodibenz[b,f]oxepin-1,3-diol (21)

[0178] Synthesis of Carboxylic Acid (14)

[0179] To a mixture of 30.0 g (F.W. 235.46, 127 mmol) of 5-10bromo-2-chlorobenzoic acid (12), 21.6 g (F.W. 154.165, 140 mmol) of3,5-dimethoxyphenol (13), 35.3 g (F.W. 138.21, 325.6 mmol) of potassiumcarbonate and 180 mL of N-methyl-2-pyrrolidone was added benzene (100mL) and the resulting solution was dried by a Dean-Stark water separator(140-170° C.) for three hours and then, 1.59 g (F.W. 63.55, 25.0 mmol)of copper (powder) and 6.05 g (F.W. 190.45, 25.0 mmol) of copper (I)iodide were added thereto and stirred at 120° C. for 1.5 hours. Thisreaction mixture was cooled by standing and ice water and ethyl acetatewere added thereto and then, the obtained solution was made pH 2 withconcentrated hydrochloric acid and filtered. The organic layer wasseparated and then, thoroughly washed with water and subjected tosalting out with a saturated sodium chloride aqueous solution. Afterdrying with anhydrous magnesium sulfate and concentration, the residuewas recrystallized from benzene to obtain 25.47 g of carboxylic acid(14). The mother liquor was purified by column chromatography (silicagel, water content of 6%; 250 g, ethyl acetate:hexane=1:2) to obtain4.58 g of crystals. Total yield: 30.05 g (67%)+9.23 g of mother liquor(purity 40%) (TLC; ethyl acetate:hexane=1:2 or 1:1).

[0180] MS(EI): 354, 352, 269

[0181] NMR (CDCl₃): 3.76 (2H, s, CH₂), 3.77 (6H, s, CH₃×2), 6.22 (2H, d,J=2.5 Hz, Ar—H), 6.33 (1H, d, J=2.5 Hz, Ar—H), 6.85 (1H, d, J=8.5 Hz,Ar—H), 7.57 (1H, dd, J=8.5, 2.2 Hz, Ar—H), 8.26 (1H, d, J=2.2 Hz, Ar—H)

[0182] Synthesis of Alcohol (15)

[0183] To a solution of 21.5 g (F.W. 353.168, 60.9 mmol) of carboxylicacid (14) in 75 mL of tetrahydrofuran was added potionwise 2.65 g (F.W.37.83, 70.05 mmol) of sodium borohydride at room temperature and then,9.49 mL (F.W. 141.93, d=1.154, 77.16 mmol) of boron trifluoride diethyletherate was added dropwise thereto. The resulting solution was stirredat room temperature for one hour. A 200 mL of ice water was slowly addedto the reaction solution. The resulting solution was extracted withethyl acetate and the extract was washed with a saturated sodiumchloride aqueous solution three times. After drying with anhydrousmagnesium sulfate, the solvent was removed under reduced pressure. Theresidue was recrystallized from benzene-diisopropyl ether to obtain19.04 g (98%) of alcohol (15). (TLC; ethyl acetate:hexane=1:4).

[0184] MS(EI): 340, 338, 291, 289

[0185] NMR (CDCl₃): 3.75 (6H, s, CH₃×2), 4.70 (2H, s, CH₂), 6.02 (2H, d,J=2.5 Hz, Ar—H), 6.07 (1H, d, J=2.5 Hz, Ar—H), 6.85 (1H, d, J=8.5 Hz,Ar—H), 7.39 (1H, dd, J=8.5, 2.2 Hz, Ar—H), 7.64 (1H, d, J=2.2 Hz, Ar—H)

[0186] Synthesis of Chloride (16)

[0187] By azeotropy with benzene, 20.0 g (F.W. 339.185, 62.6 mmol) ofalcohol (15) was dried. A 40 mL of benzene and 10 mL of methylenechloride to which 5.63 mL (F.W. 118.97, d=1.631, 76.7 mmol) of thionylchloride and 5.6 mL of methylene chloride were added at 0° C. were addedto the dried alcohol to give a mixture. The mixture was stirred at thesame temperature for 30 minutes. The reaction solution was furtherstirred at room temperature overnight. To the reaction mixture was addedice water and the resulting solution was extracted with ethyl acetateand the extract was washed with water and then with a saturated sodiumchloride aqueous solution. After drying with anhydrous magnesiumsulfate, the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography (developing solvent; ethylacetate:hexane=1:4) to obtain 14.03 g (65%) of chloride (16). (TLC;ethyl acetate:hexane=1:4)

[0188] NMR (CDCl₃): 3.75 (6H, s, CH₃×2), 4.49(2H, s, CH₂), 6.16 (2H, d,J=2.5 Hz, Ar—H), 6.25 (1H, d, J=2.5 Hz, Ar—H), 6.78 (1H, d, J=8.7 Hz,Ar—H), 7.35 (1H, dd, J=8.7, 2.4 Hz, Ar—H), 7.57(1H, d, J=2.4 Hz, Ar—H)

[0189] Synthesis of Nitrile Compound (17)

[0190] In 30 mL of dimethyl sulfoxide was dissolved 27.9 g (F.W.357.631, 78.0 mmol) of chloride (16). To this solution was added 5.49 g(F.W. 49.01, 112.0 mmol) of sodium cyanide and stirred at 80° C. for onehour. Under cooling with ice water, water was added to the reactionsolution and then, the resulting solution was extracted with ethylacetate three times. The extract was washed with water and then with asaturated sodium chloride aqueous solution. After drying with anhydrousmagnesium sulfate, the solvent was removed under reduced pressure. Theresidue was recrystallized from methylene chloride-hexane to obtain16.91 g (65%) of nitrile compound (17). (TLC; ethyl acetate:hexane=1:4).

[0191] MS(EI): 349, 347

[0192] NMR (CDCl₃): 3.70(2H, s, CH₂), 3.74 (3H, s, CH₃), 3.75 (3H, s,CH₃), 6.11 (2H, d, J=2.5 Hz, Ar—H), 6.26(1H, d, J=2.5 Hz, Ar—H), 6.81(1H, d, J=8.5 Hz, Ar—H), 7.40(1H, dd, J=8.5, 2.2 Hz, Ar—H ), 7.62(1H, d,J=2.2 Hz, Ar—H)

[0193] Synthesis of Phenylacetic Acid (18)

[0194] To 14.00 g (F.W. 348.196, 40.0 mmol) of nitrile compound (17)were added 33.6 mL of ethanol and 33.6 mL of a 6N sodium hydroxideaqueous solution [8.06 g (F.W. 40.00, 201.5 mmol) of sodium hydroxidebeing dissolved in water] and stirred at 110° C. overnight. To thereaction solution was added ice and the resulting solution was made pH 2with concentrated hydrochloric acid. The reaction solution thus obtainedwas extracted with ethyl acetate and the extract was washed with waterand then with a saturated sodium chloride aqueous solution. After dryingwith anhydrous magnesium sulfate, the solvent was completely removed andthe residue was crystallized from benzene-hexane to obtain 13.33 g (90%)of phenylacetic acid (18). (TLC; ethyl acetate:hexane=1:2 or 1:1).

[0195] NMR (CDCl₃): 3.70 (3H, s, CH₃), 3.90 (3H, s, CH₃), 3.95 (1H, s,CH₂), 6.26 (1H, d, J=2.5 Hz, Ar—H), 6.46 (1H, d, J=2.5 Hz, Ar—H), 7.08(1H, d, J=8.5 Hz, Ar—H), 7.33 (1H, dd, J=8.5, 2.3 Hz, Ar—H ), 7.41 (1H,d, J=2.3 Hz, Ar—H), 12.91 (1H, s, OH)

[0196] Synthesis of Cyclized Compound (19)

[0197] To 11.75 g (F.W. 367.195, 32.0 mmol) of carboxylic acid (18) wasadded 60 mL of methanesulfonic acid to dissolve carboxylic acid (18).The resulting solution was stirred at 40° C. for three days. To thereaction solution was added 300 mL of ice water to deposit a cyclizedcompound. The deposited cyclized compound was separated by filtrationand extracted with ethyl acetate and treated by the conventional methodto obtain a crude product. This' crude product was recrystallized fromhexane-methylene chloride to obtain 6.0 g (54%) of cyclized compound(19). (TLC; ethyl acetate:hexane=1:2).

[0198] MS(EI): 349, 347, 269

[0199] NMR (CDCl₃): 3.84 (3H, s, CH,), 3.90 (3H, s, CH₃), 3.95 (1H, s,CH₂), 6.26 (1H, d, J=2.5 Hz, Ar—H), 6.46 (1H, d, J=2.5 Hz, Ar—H), 7.08(1H, d, J=8.5 Hz, Ar—H), 7.33 (1H, dd, J=8.5, 2.3 Hz, Ar—H), 7.41 (1H,d, J=2.3 Hz, Ar—H), 12.91 (1H, s, OH)

[0200] Synthesis of2-Bromo-7,9-dihydroxy-10,11-dihydrodibenz[b,f]oxepin-10-one (20)

[0201] To 395 mg (F.W. 349.18, 1.13 mmol) of dimethoxylated compound(19) was added 2.0 g of pyridine hydrochloride and stirred at 195° C.for 1.5 hours under heating and then, ice water was slowly added. Theresulting solution was extracted with ethyl acetate and the extract waswashed with 1N hydrochloric acid, water and a saturated sodium chlorideaqueous solution in the order named. After drying with anhydrousmagnesium sulfate, the dried extract was concentrated. The residue waspurified by silica gel column chromatography (developing solvent; ethylacetate:hexane=1:2). Furthermore, the product thus obtained wasrecrystallized from diisopropyl ether-hexane to obtain 223 mg (61%) ofthe title compound. (TLC; ethyl acetate:hexane=1:2).

[0202] Melting Point: 194-195° C.

[0203] MS(EI): 322, 320, 241

[0204] NMR (CDCl₃): 4.03 (2H, s, CH₂), 5.88 (1H, s, OH), 6.17 (1H, d,J=2.5 Hz, Ar—H), 6.35 (1H, d, J=2.5 Hz, Ar—H), 7.10 (1H, d, J=8.5 Hz,Ar—H), 7.36 (1H, dd, J=8.5, 2.3 Hz, Ar—H), 7.43 (1H, d, J=2.3 Hz, Ar—H),12.91 (1H, s, OH)

[0205] Synthesis of 8-Bromo-10,11-dihydrodibenz[b,f]oxepin-1,3-diol (21)

[0206] To 2.00 g (F.W. 321.126, 6.23 mmol) of dimethoxylated compound(19) was added 50 mL of methanol and stirred. The obtained suspensionwas cooled to 0° C. Thereto 500 mg of sodium borohydride was dividedlyadded several times. The reaction solution was returned to roomtemperature and stirred for one hour. To the reaction solution was addeddilute hydrochloric acid to stop the reaction, and methanol wasdistilled off under reduced pressure. The resulting reaction solutionwas partitioned with ethyl acetate. The organic layer was washed withwater and then with a saturated sodium chloride aqueous solution, andsubsequently dried with anhydrous magnesium sulfate and the solvent wasdistilled off under reduced pressure to obtain an oily substance, and 10g of pyridine hydrochloride was added to the oily substance and stirredat 200° C. for two hours under heating. After completion of thereaction, the reaction solution was partitioned with ethyl acetate anddilute hydrochloric acid. The organic layer was washed with water andthen with a saturated sodium chloride aqueous solution, and subsequentlydried with anhydrous magnesium sulfate and the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (developing solvent; hexane:ethyl acetate=1:1). The oilysubstance thus obtained was dissolved in 20 mL of ethyl acetate. To theresultingsolution was added 100 mg of palladium (IV) oxide to effectcatalytic reduction at room temperature for three days. After completionof the reaction, the reaction solution was filtered and concentrated andthe residue was purified by silica gel column chromatography (developingsolvent; hexane:ethyl acetate=2:1). The product thus obtained wasrecrystallized from chloroform-hexane to obtain the title compound(901.0 mg, 52.2%) as orange plates.

[0207] Melting Point: 173.8-175.8° C.

[0208] NMR (DNSO-d₆): 2.74 (2H, t, J=6.3 Hz, CH₂), 2.99 (2H, t, J=6.3Hz, CH₂), 6.05 (1H, d, J=2.3 Hz, Ar—H), 6.10 (1H, d, J=2.3 Hz, Ar—H),7.04 (1H, d, J=8.5 Hz, Ar—H), 7.32 (1H, dd, J=8.5, 2.5 Hz, Ar—H), 7.42(1H, d, J=2.5 Hz, Ar—H), 9.19 (1H, s, Ph—OH), 9.39 (1H, s, Ph—OH)

Referential Example 5

[0209] Method of Preparing7-Bromo-10,11-dihydrodibenz[b,f]-oxepin-1,3-diol (29)

[0210] Synthesis of 4-Bromo-2-(3,5-dimethoxyphenoxy)benzoic Acid (22)

[0211] To a mixture of 88.3 g (F.W. 235.46, 375 mmol) of4-bromo-2-chlorobenzoic acid (3), 57.8 g (F.W. 154.165, 375 mmol) of3,5-dimethoxyphenol (13), 93.2 g (F.W. 138.21, 670 mmol) of potassiumcarbonate and 400 mL of N-methyl-2-pyrrolidone was added benzene (200mL), and the resulting solution was dried by a Dean-Stark waterseparator (140-170° C.) for three hours and then, 6.0 g (F.W. 63.55,93.7 mmol) of copper (powder) and 17.8 g (F.W. 190.45, 93.7 mmol) ofcopper (I) iodide were added thereto and stirred at 120° C. for 30minutes. This reaction mixture was cooled by standing and ice water andethyl acetate were added thereto and then, the obtained solution wasmade pH 2 with concentrated hydrochloric acid and filtered. The organiclayer was separated and then, thoroughly washed with water and subjectedto salting out with a saturated sodium chloride aqueous solution. Theresulting solution was dried with anhydrous magnesium sulfate andconcentrated and the residue was purified by silica gel columnchromatography (developing solvent; ethyl acetate:hexane=1:3) andrecrystallized from ethyl acetate-hexane to obtain 75.4 g (57%) adesired compound (20). (TLC; ethyl acetate:hexane=1:2 or 1:1)

[0212] Melting Point: 112-117° C.

[0213] UV (EtOH)λ_(max)(ε): 292 (2000)nm

[0214] IR (KBr) ν_(max) cm⁻¹: 3411, 1699, 1605

[0215]¹H NMR (400 MHz, CDCl₃) δ: 3.75 (2H, s, CH₂), 3.77 (6H, s, CH₃×2),6.23 (1H, d, J=2.1 Hz, Ar—H), 6.34 (1H, d, J=2.1 Hz, Ar—H), 7.09 (2H, m,Ar—H), 7.32 (1H, m, Ar—H), 7.98 (1H, m, Ar—H)

[0216] MS(EI) m/z: 354, 352, 309, 307

[0217] Synthesis of 4-Bromo-2-(3,5-dimethoxyphenoxy)benzyl Alcohol (23)

[0218] To a solution of 75.4 g (F.W. 353.168, 213 mmol) of4-bromo-2-(3,5-dimethoxyphenoxy)benzoic acid (22) in 300 mL oftetrahydrofuran was added 8.9 g (F.W. 37.83, 235 mmol) of sodiumborohydride portionwise at room temperature and then, 31 mL (F.W.141.93, d=1.154, 252 mmol) of boron trifluoride diethyl etherate wasadded thereto dropwise. The resulting solution was stirred at roomtemperature for one hour. To this reaction solution was added 200 mL ofice water slowly. The resulting solution was extracted with ethylacetate and the extract was washed with a saturated sodium chlorideaqueous solution three times. After drying with anhydrous magnesiumsulfate, the solvent was removed under reduced pressure. The residue wasrecrystallized from benzene-diusopropyl ether to obtain 46.6 g (64%) ofalcohol (23). (TLC; ethyl acetate:hexane=1:4).

[0219] MS(EI) m/z: 340, 338

[0220] Synthesis of 4-Bromo-2-(3,5-dimethoxyphenoxy)benzyl Bromide (24)

[0221] In an argon atmosphere, 4.7 mL (F.W. 270.70, d=2.850, 49.5 mmol)of phosphorus tribromide was added to a solution of 46 g (F.W. 339.19,135 mmol) of alcohol (23) in 100 mL of methylene chloride at 0° C. andstirred at room temperature for 30 minutes. To the reaction mixture wasadded ice water and the resulting solution was further stirred at roomtemperature for 30 minutes. The obtained solution was extracted withethyl acetate and the extract was washed with water and then with asaturated sodium chloride aqueous solution. The resulting extract wasdried with anhydrous magnesium sulfate and then, concentrated. Theresidue was purified by silica gel column chromatography (developingsolvent; ethyl acetate:hexane=1:5) to obtain 44.6 g (84%) of a bromide(24). (TLC; ethyl acetate:hexane=1:4) Synthesis of4-Bromo-2-(3.5-dimethoxyphenoxy)benzyl Nitrile (25)

[0222] In 50 mL of dimethyl sulfoxide was dissolved 44.6 g (F.W.357.631, 111 mmol) of bromide (24). To this solution was added 8.15 g(F.W. 49.01, 166 mmol) of sodium cyanide and stirred at 80° C. for onehour. Under cooling with ice water, to the reaction solution was addedwater and then, the resulting solution was extracted with ethyl acetatethree times. The extract was washed with water and then with a saturatedsodium chloride aqueous solution. After drying with anhydrous magnesiumsulfate, the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography (developing solvent; ethylacetate:hexane=1:4) to obtain 34.5 g (89%) of nitrile compound (25).(TLC; ethyl acetate:hexane=1:4).

[0223]¹H NMR (400 MHz, CDCl₃) δ: 3.70(2H, s, CH₂), 3.77 (6H, s, CH₃×2),6.14 (1H, d, J=2.1 Hz, Ar—H), 6.28 (1H, d, J=2.1 Hz, Ar—H), 7.02 (1H, m,Ar—H), 7.15 (1H, m, Ar—H), 7.21 (1H, m, Ar—H)

[0224] MS(EI) m/z: 349, 347, 269

[0225] Synthesis of 4-Bromo-2-(3,5-dimethoxyphenoxy)phenylacetic Acid(26)

[0226] To 34.5 g (F.W. 348.196, 99.1 mmol) of nitrile compound (25) wereadded 83 mL of ethanol and 83 mL [19.9 g (F.W. 40.00, 497 mmol) ofsodium hydroxide] of a 6N sodium hydroxide aqueous solution and stirredat 110° C. overnight. To the reaction solution was added ice and theobtained solution was made pH 2 with concentrated hydrochloric acid. Thereaction solution thus obtained was extracted with ethyl acetate and theextract was washed with water and then with a saturated sodium chlorideaqueous solution. After drying with anhydrous magnesium sulfate, thesolvent was completely removed and the residue was purified by silicagel column chromatography (developing solvent; ethyl acetate:hexane=2:3)and crystallized from ethyl acetate-hexane to obtain 27.3 g (75%) ofcarboxylic acid (26). (TLC; ethyl acetate:hexane=1:2 or 1:1).

[0227] Melting Point: 121.9-123.6° C.

[0228] HV (EtOH)λ_(max)(ε): 272 (2200)nm

[0229] IR (KBr)ν_(max) cm⁻¹: 2954, 1705, 1606, 1576

[0230]¹H NMR (400 MHz, CDCl₃) δ: 3.60 (2H, s, CH₂), 3.60 (6H, s, CH₃×2),6.13 (1H, d, J=2.1 Hz, Ar—H), 6.25 (1H, d, J=2.1 Hz, Ar—H), 7.02 (1H, m,Ar—H), 7.15 (1H, m, Ar—H), 7.21 (1H, m, Ar—H),

[0231] MS(EI) m/z: 368, 366

[0232] Synthesis of3-Bromo-7,9-dimethoxy-10,11-dihydrodibenz[b.f]oxepin-10-one (27)

[0233] To 27.3 g (F.W. 367.195, 74.3 mmol) of carboxylic acid (26) wasadded 140 mL of methanesulfonic acid to dissolve carboxylic acid (26).This solution was stirred at 40° C. for three days. To the resultingreaction solution was added 300 mL of ice water to deposit a cyclizedcompound. The cyclized compound was separated by filtration andextracted with ethyl acetate and treated according to the conventionalmethod to obtain a crude product. This crude product was purified bysilica gel column chromatography (developing solvent; ethylacetate:hexane=1:2) and recrystallized from hexane-ethyl acetate toobtain 17.1 g (66%) of cyclized compound (27). (TLC; ethylacetate:hexane=1:2).

[0234] Melting Point: 95-103° C.

[0235] UV (EtOH)λ_(max)(ε): 272 (2800)nm

[0236] IR (KBr)ν_(max) cm⁻: 2977, 1679, 1604

[0237]¹H NMR (400 MHz, CDCl₃) δ: 3.84 (3H, s, CH₃), 3.88 (3H, s, CH₃),3.95 (2H, s, CH₂), 6.27 (1H, d, J=2.1 Hz, Ar—H), 6.47 (1H, d, J=2.1 Hz,Ar—H), 7.15 (1H, m, Ar—H), 7.30 (1H, m, Ar—H), 7.40 (1H, m, Ar—H),

[0238] MS(EI) m/z: 350, 348

[0239] Synthesis of3-Bromo-7,9-dihydroxy-10,11-dihydrodibenz[b,f]oxepin-10-one (28)

[0240] To 395 mg (F.W. 349.18, 15.75 mmol) of dimethoxylated compound(27) was added 2.0 g of pyridine hydrochloride and stirred at 195° C.for 1.5 hours and then, ice water was slowly added thereto. Theresulting solution was extracted with ethyl acetate and the extract waswashed with 1N hydrochloric acid, water and a saturated sodium chlorideaqueous solution in the order named. The extract thus washed was driedwith anhydrous magnesium sulfate and then, concentrated. The residue waspurified by silica gel column chromatography (developing solvent; ethylacetate:hexane=1:2). Furthermore, the product thus obtained wasrecrystallized from dioxane and dioxane-hexane to obtain 223 mg (61%) ofthe title compound. (TLC; ethyl acetate:hexane=1:2).

[0241] Melting Point: 194-195° C.

[0242]¹H NMR (400 MHz, CDCl₃) δ: 4.03 (2H, s, CH₂), 6.09 (1H, d, J=2.1Hz, Ar—H), 6.39 (1H, d, J=2.1 Hz, Ar—H), 7.43 (2H, m, Ar—H), 7.64 (1H,m, Ar—H), 11.07 (1H, s, OH), 12.95 (1H, s, OH)

[0243] MS(EI) m/z: 322, 320

[0244] Synthesis of 7-Bromo-10,11-dihydrodibenz[b,f]oxepin-1,3-diol (29)

[0245] To 5.5 g (F.W. 349.18, 15.75 mmol) of dimethoxylated compound(27) was added 80 mL of methanol and stirred. The obtained suspensionwas cooled to 0° C. Thereto 890 mg of sodium borohydride was dividedlyadded several times. The reaction solution was returned to roomtemperature and stirred for one hour. To the reaction solution was addeddilute hydrochloric acid to stop thereaction, and methanol was distilledoff under reduced pressure. To the resulting reaction solution was addedethyl acetate to effect partition. The organic layer was washed withwater and then with a saturated sodium chloride aqueous solution, andsubsequently dried with anhydrous magnesium sulfate and the solvent wasdistilled off under reduced pressure to obtain an oily substance, and 20mL of pyridine and 3.6 g of tosyl chloride were added to the oilysubstance and stirred at 90° C. overnight. The reaction solution waspartitioned with ethyl acetate and dilute hydrochloric acid. The organiclayer was washed with water and then with a saturated sodium chlorideaqueous solution, and subsequently dried with anhydrous magnesiumsulfate and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (developingsolvent; hexane:ethyl acetate=5:1)(4.96 g, yield 95%). The oilysubstance thus obtained was dissolved in 50 mL of ethyl acetate and 150mg of palladium (IV) oxide added thereto to effect catalytic reductionat room temperature for one day. After completion of the reaction thereaction solution was filtered and concentrated and the residue waspurified by silica gel column chromatography (developing solvent:hexane:ethyl acetate=10:1) (4.21 g, yield 84%; melting point 60.0-66.2°C.). To the obtained crystals 150 mg (F.W. 335.20, 0.45 mmol) was added2 g of pyridine hydrochloride and the resulting solution was stirred at200° C. under heating for two hours. After completion of the reaction,the reaction solution was partitioned with ethyl acetate and dilutehydrochloric acid. The organic layer was washed with water and then witha saturated sodium chloride aqueous solution, and subsequently driedwith anhydrous magnesium sulfate and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (developing solvent; hexane:ethyl acetate=1:1). Theproduct thus obtained was recrystallized from chloroform-hexane toobtain 80 mg (58%) of the title compound as pink plates.

[0246] Melting Point: 177.5-179.5° C.

[0247]¹H NMR (90 Mz, DMSO-d₆) δ: 2.7-2.9(2H, m, CH₂), 2.9-3.1 (2H, m,CH₂), 6.0-6.2 (2H, m, Ar—H), 7.1-7.4 (3H, m, Ar—H), 9.22 (1H, s, OH),9.41 (1H, s, OH)

[0248] MS(EI) m/z: 308, 306, 227

Referential Example 6

[0249] Method of Preparing1-Chloro-7,9-dihydroxy-10,11-dihydrodibenz[b,f]oxepin-10-one (38)

[0250] Synthesis of Carboxylic Acid (31)

[0251] To a mixture of 9.32 g (F.W. 191.01, 48.8 mmol) of2,6-dichlorobenzoic acid (30), 6.60 g (F.W. 154.165, 4.29 mmol) of3,5-dimethoxyphenol (13), 9.32 g (F.W. 138.21, 67.4 mmol) of potassiumcarbonate and 56 mL of N-methyl-2-pyrrolidone was added benzene (40 mL),and the resulting solution was dried by a Dean-Stark water separator(140-170° C.) for three hours and then, 614 mg (F.W. 63.55, 9.67 mmol)of copper (powder) and 2.30 mg (F.W. 190.45, 12.1 mmol) of copper (I)iodide were added thereto and the obtained solution was stirred at 140°C. for one hour. This reaction mixture was cooled by standing and icewater and ethyl acetate were added thereto and then, the resultingsolution was made pH 2 with concentrated hydrochloric acid and filtered.The organic layer was separated and then, thoroughly washed with waterand subjected to salting out with a saturated sodium chloride aqueoussolution. The resulting solution was dried with anhydrous magnesiumsulfate and concentrated. The residue (17 g) was purified by columnchromatography (silica gel, water content of 6%; 340 g, ethylacetate:hexane=1:2) to obtain 5.05 g (38%) of crystals (31).

[0252] Synthesis of Esterified Compound (32)

[0253] To a mixed solution of 2.5 g (F.W. 353.168, 8.10 mmol) ofcarboxylic acid (31) in 10 mL of dichloromethane and 10 mL of methanolwas added an ether solution of diazomethane until the yellow colordisappeared. The reaction solution was concentrated and purified bycolumn chromatography (silica gel; 90 g, ethyl acetate:hexane=1:4) toobtain 2.507 g (98%) of an esterified compound (32)(TLC; ethylacetate:hexane=1:4).

[0254] Synthesis of Alcohol (33)

[0255] To a mixture of 250 mg (F.W. 37.83, 6.60 mmol) of lithiumaluminum hydride and 10 mL of diethyl ether was added a solution of 2.51g (F.W. 322.744, 7.76 mmol) of esterified compound (32) in ether (5+3mL) portionwise at 0° C. under stirring. After stirring at roomtemperature for three hours, a 90% methanol solution and a saturatedammonium chloride aqueous solution were added to the resulting reactionsolution. The organic layer was separated and washed with a saturatedsodium chloride aqueous solution three times. After drying withanhydrous magnesium sulfate, the solvent was removed under reducedpressure. The residue was purified by column chromatography (silica gel;150 g, ethyl acetate:hexane-3:7) to obtain 1.53 g (64%) of alcohol (33).(TLC; ethyl acetate:hexane=1:4).

[0256] Synthesis of Bromide (34)

[0257] By azeotropy with benzene, 2.24 g (F.W. 308.761, 7.28 mmol) ofalcohol (33) was dried. A 5 mL of methylene chloride to which 0.254 mL(F.W. 270.70, d=2.85, 2.67 mmol) of phosphorus tribromide had been addedand 5.6 mL of methylene chloride were added thereto at 0° C. and stirredat room temperature for two hours. To the reaction mixture was added icewater and the resulting solution was extracted with ethyl acetate andthe extract was washed with water and then with a saturated sodiumchloride aqueous solution. After drying with anhydrous magnesiumsulfate, the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography (developing solvent; ethylacetate:hexane=1:4) to obtain 2.58 g (99%) of bromide (34) as crystals.(TLC; ethyl acetate:hexane=1:4)

[0258] Synthesis of Nitrile Compound (35)

[0259] In 5 mL of dimethyl sulfoxide was dissolved 2.58 g (F.W. 357.631,7.21 mmol) of bromide (34). To this solution was added 530 mg (F.W.49.01, 10.82 mmol) of sodium cyanide and stirred at 800C for 30 minutes.Under cooling with ice water, to the reaction solution was added waterand then, the resulting solution was extracted with ethyl acetate threetimes. The extract was washed with water and then with a saturatedsodium chloride aqueous solution. After drying with anhydrous magnesiumsulfate, the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography (developing solvent; ethylacetate:hexane=1:4) to obtain 1.95 g (89%) of nitrile compound (35).(TLC; ethyl acetate:hexane=1:4).

[0260] Synthesis of Phenylacetic Acid (36)

[0261] To 1.93 g (F.W. 303.745, 6.35 mmol) of nitrile compound (35) wereadded 4.56 mL of ethanol and 4.56 mL [1.13 g (F.W. 40.00, 28.3 mmol) ofsodium hydroxide] of a 6N sodium hydroxide and stirred at 110° C.overnight. To the reaction solution was added ice and the resultingsolution was made pH 2 with concentrated hydrochloric acid. The reactionsolution thus obtained was extracted with ethyl acetate and the extractwas washed with water and then with a saturated sodium chloride aqueoussolution. After drying with anhydrous magnesium sulfate, the solvent wascompletely removed under reduced pressure and the residue wascrystallized from benzene-hexane to obtain 1.36 g (66%) of phenylaceticacid (36). (TLC; ethyl acetate:hexane=1:2 or 1:1).

[0262] Synthesis of Cyclized Compound (37)

[0263] To 1.30 g (F.W. 332.74, 4.03 mmol) of carboxylic acid (36) wasadded 6 mL of toluene to dissolve carboxylic acid (36) and then,polyphosphoric acid (10 mL of phosphoric acid and 7 g of phosphoruspentoxide having been heated at 150° C.) was added thereto and theobtained solution was concentrated. This solution was stirred at 100° C.for 1.5 hours. To the resulting reaction solution was added ice waterand the solution thus obtained was extracted with ethyl acetate andtreated according to the conventional method to obtain a crude product.This crude product was recrystallized from hexane-methylene chloride toobtain 1.17 g (85%) of cyclized compound (37). (TLC; ethylacetate:hexane=1:2).

[0264] Synthesis of1-Chloro-7,9-dihydroxy-10,11-dihydrodibenz[b.f]oxepin-10-one (38)

[0265] To 150 mg (F.W. 304.729, 0.492 mmol) of dimethoxylated compound(37) and 0.15 mL of benzene was added 2.0 g of pyridine hydrochlorideand stirred at 195° C. for 1.5 hours with heating and then, ice waterwas slowly added thereto. The resulting solution was extracted withethyl acetate and the extract was washed with 1N hydrochloric acid,water and a saturated sodium chloride aqueous solution in the ordernamed. After drying with anhydrous magnesium sulfate, the dried extractwas concentrated. The residue was purified by silica gel columnchromatography (developing solvent; ethyl acetate:hexane=1:2).Furthermore, the product thus obtained was recrystallized fromdichloromethane-hexane to obtain 104 mg (77%) of the title compound.(TLC; ethyl acetate:hexane=1:2).

Referential Example 7

[0266] Method of Preparing of9-Chloro-10,11-dihydrodibenz[b,f]oxepin-1,3-diol (40)

[0267] Reduction of Ketone of Ring B

[0268] In 20 mL of ethylene glycol was dissolved 475 mg (F.W. 304.729,1.56 mmol) of ring B-ketone compound (37) and 2.25 mL (F.W. 50.06.d=1.032, 46.5 mmol) of hydrazine-monohydrate and 3.05 g (F.W. 56.11,54.3 mmol) of potassium hydroxide were added thereto and stirred at 70°C. for 4.5 hours. After raising the temperature up to 140° C., thereaction solution was further stirred for two hours. Under cooling withice, the reaction solution was neutralized by addition of 4Nhydrochloric acid. The reaction solution thus neutralized was extractedwith ethyl acetate and the extract was washed with water and then with asaturated sodium chloride aqueous solution. After drying with anhydroussodium sulfate, the solvent was removed under reduced pressure. Theresidue was purified by silica gel column chromatography (developingsolvent; hexane:ethyl acetate=19:1) to obtain 347 mg (F.W. 290.746, 1.19mmol, 76%) of a reduced compound (39).

[0269] Deprotection

[0270] To 347 mg (F.W. 290.746, 1.19 mmol) of dimethoxy compound (39)was added 3.5 g of pyridine hydrochoride and stirred at 200° C. for twohours with heating and then, ice water was slowly added thereto. Thereaction solution was extracted with ethyl acetate and the extract waswashed with 1N hydrochloric acid, water and a saturated sodium chlorideaqueous solution in the order named. After drying with anhydrous sodiumsulfate, the extract thus washed was concentrated. The residue waspurified by silica gel column chromatography (developing solvent; ethylacetate:hexane=3:1) and further recrystallized from chloroform-hexane toobtain 225 mg (F.W. 262.692, 0.86 mmol, 72%) of the title compound (40).

EXAMPLES

[0271] The present invention will now be explained in more detail basedon Examples but the present invention is not limited to them or the likeand may be changed without departing from the scope of the presentinvention. The elution in the chromatography of Example was carried outunder observation by thin-layer chromatography (TLC) unless expresslystated otherwise. In the TLC observation, “60F₂₅₄” of Merck was used asthe TLC plate and as the developing solvent, a solvent which was used asthe eluting solvent in column chromatography was used. Further, an UVdetector was employed in detection. As the silica gel for the columnchromatography, “Silica Gel 60” (70 to 230 mesh) of Merck or“Microsphere Gel D75-60A” of Asahi Glass was used. The term “roomtemperature” means about 10° C. to about 35° C.

Example 1

[0272] Preparation of2-Methylthio-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one(Compound of Example 1)

[0273] Synthesis of Carboxylic Acid (42)

[0274] To a mixture of 60.8 g (F.W. 202.66, 0.30 mmol) of5-thiomethyl-2-chlorobenzoic acid (41), 21.0 g (F.W. 338.448, 0.15 mmol)of 3,5-dimethoxy disulfide (9), 21.0 g (F.W. 138.21, 0.15 mmol) ofpotassium carbonate and 300 mL of N-methyl-2-pyrrolidone was addedbenzene (100 mL×3), and the resulting mixture was subjected toazeotropic drying by a Dean-Stark water separator and then, heated at135° C. To this reaction solution were added 9.53 g (F.W. 63.55, 0.15mol) of copper (powder) and 28.57 g (F.W. 190.45, 0.15 mol) of copper(I) iodide and stirred at 135° C. for 5.5 hours. This reaction mixturewas cooled by standing and ice water and ethyl acetate were addedthereto and then, the resulting solution was made pH 2 with concentratedhydrochloric acid and filtered. The organic layer was separated andthen, thoroughly washed with water and subjected to salting out with asaturated sodium chloride aqueous solution. After drying with anhydrousmagnesium sulfate and concentrating, the resulting crude carboxylic acidwas recrystallized from 2-butanone-isopropyl ether to obtain 65.08 g ofcarboxylic acid (42). Total yield: 65.08 g(65%)+11.03 g of mother liquor(purity 40%) (TLC; ethyl acetate:hexane=1:2 or 1:1).

[0275] MS(EI): 336, 318, 303, 244

[0276] NMR (CDCl₃): 2.48 (3H, s, CH₃), 3.78 (6H, s, CH₃×2), 6.50 (1H, d,J=2.2 Hz, Ar—H), 6.69 (1H, d, J=2.2 Hz, Ar—H), 6.91 (1H, d, J=8.5 Hz,Ar—H), 7.22 (1H, dd, J=8.5, 2.2 Hz, Ar—H), 7.97 (1H, d, J=2.2 Hz, Ar—H)

[0277] Synthesis of Alcohol (43)

[0278] To a solution of 50.45 g (F.W. 336.432, 150 mmol) of carboxylicacid (42) in 200 mL of tetrahydrofuran was added 6.24 g (F.W. 37.83,165.0 mmol) of sodium borohydride in small portions at room temperatureand then, 20.29 mL (F.W. 141.93, d=1.154, 165.0 mmol) of borontrifluoride diethyl etherate was added dropwise thereto. The resultingmixture was stirred at room temperature for one hour. To the reactionsolution was slowly added ice water. The resulting solution wasextracted with ethyl acetate and washed with a saturated sodium chlorideaqueous solution three times. After drying with magnesium sulfate, thesolvent was removed under reduced pressure. The residue wasrecrystallized from diisopropyl ether to give 46.23 g of alcohol(43).These crystals were recrystallized from ethyl acetate-hexane again toobtain 43.61 g (77%) of a product. (TLC; ethyl acetate:hexane=1:2).

[0279] MS(EI): 322, 303, 289, 273

[0280] NMR (CDCl₃): 2.51 (3H, s, CH₃), 3.71 (6H, s, CH₃×2), 4.74 (2H, d,J=6.3 Hz, CH₂), 6.26 (3H, s, Ar—H), 6.85 (1H, dd, J=8.5, 2.2 Hz, Ar—H),7.40 (1H, d, J=2.2 Hz, Ar—H), 7.42 (1H, d, J=8.5 Hz, Ar—H)

[0281] Synthesis of Bromide (44)

[0282] To a solution of 59.06 g(F.W. 322.449, 175.5 mmol) of alcohol(43) in methylene chloride (127 mL) was added 6.4 mL (F.W. 118.97,d=1.631, 64.4 mmol) of phosphorus tribromide at 0° C. and stirred at thesame temperature for 30 minutes. The reaction solution was furtherstirred at room for 15 minutes. To the reaction mixture was added icewater and the resulting solution was extracted with ethyl acetate andwashed with water and then with a saturated sodium chloride aqueoussolution. After drying with anhydrous magnesium sulfate, the solvent wasremoved under reduced pressure. The residue was purified by silica gelcolumn chromatography (developing solvent; ethyl acetate:hexane=1:5) andthen, recrystallized from ethyl acetate-hexane to obtain 57.74 g (82%)of bromide (44). (TLC; ethyl acetate:hexane=1:4)

[0283] MS(EI): 386, 384

[0284] NMR (CDCl₃): 2.50 (3H, s, CH₃), 3.73 (6H, s, CH₃×2), 4.64(2H, s,CH₂), 6.28 (1H, d, J=2.2 Hz, Ar—H), 6.33 (2H, d, J=2.2 Hz, Ar—H), 7.12(1H, dd, J=8.2, 2.4 Hz, Ar—H), 7.33 (1H, d, J=8.2 Hz, Ar—H ), 7.35(1H,d, J=2.4 Hz, Ar—H)

[0285] Synthesis of Nitrile Compound (45)

[0286] In 127 mL of dimethyl sulfoxide was dissolved 57.74 g (F.W.385.346, 149.8 mmol) of bromide (44). To this solution was added 11.02 g(F.W. 49.01, 224.8 mmol) of sodium cyanide and stirred at 80° C. for 45minutes. Under cooling with ice water, to the reaction solution wasadded water and then, the obtained solution was extracted with ethylacetate three times. The extract was washed with water and then with asaturated sodium chloride aqueous solution. After drying with anhydrousmagnesium sulfate, the solvent was removed under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to obtain 34.83 g(70%) of nitrile compound (45). (TLC; ethyl acetate:hexane=1:4).

[0287] MS(EI): 331

[0288] NMR (CDCl₃): 2.53 (3H, s, CH₃), 3.72 (6H, s, CH₃), 3.85 (3H, s,CH₃), 6.20 (2H, d, J=2.5 Hz, Ar—H), 6.27 (1H, d, J=2.5 Hz, Ar—H), 7.19(1H, dd, J=8.5, 2.3 Hz, Ar—H), 7.44 (1H, d, J=2.3 Hz, Ar—H ), 7.45 (1H,d, J=8.5 Hz, Ar—H)

[0289] Synthesis of Phenylacetic Acid (46)

[0290] To 30.07 g (F.W. 331.46, 90.8 mmol) of nitrile compound (45) wereadded 75 mL of ethanol and 75 mL of a 6N sodium hydroxide aqueoussolution [18.06 g (F.W. 40.00, 450 mmol) of sodium hydroxide] andstirred at 110° C. overnight. To the reaction solution was added ice andthe resulting solution was made pH 2 with concentrated hydrochloricacid. The reaction solution thus obtained was extracted with ethylacetate and the extract was washed with water and then with a saturatedsodium chloride aqueous solution. After drying with anhydrous magnesiumsulfate, the solvent was completely removed under reduced pressure andthe residue was crystallized from benzene-hexane to obtain 28.86 g (91%)of phenylacetic acid (46). (TLC; ethyl acetate:hexane=1:2 or 1:1).

[0291] MS(EI): 350, 273

[0292] NMR (CDCl₃): 2.49 (3H, s, CH₃), 3.70 (6H, s, CH₃), 3.84 (1H, s,CH₂), 6.25 (3H, m, Ar—H), 7.15 (1H, dd, J=8.5, 2.3 Hz, Ar—H), 7.21 (1H,d, J=2.3 Hz, Ar—H), 7.42 (1H, d, J=8.5 Hz, Ar—H), 12.91 (1H, s, OH)

[0293] Synthesis of Cyclized Compound (47)

[0294] To 27.89 g (F.W. 350.459, 32.0 mmol) of carboxylic acid (46) wasadded 140 mL of methanesulfonic acid to dissolve carboxylic acid (46).The resulting solution was stirred at 40° C. for one day. To thereaction solution was added ice water to deposit a cyclized compound.The deposited cyclized compound was separated by filtration andextracted with ethyl acetate and treated by the conventional method toobtain a crude product. This crude product was recrystallized fromhexane-methylene chloride to obtain 15.22 g (58%) of cyclized compound(47). (TLC; ethyl acetate:hexane=1:2).

[0295] MS(EI): 332, 347, 269

[0296] NMR (CDCl₃): 2.49 (3H, s, CH₃), 3.81 (3H, s, CH3), 3.85 (3H, s,CH₃), 4.19 (1H, s, CH₂), 6.36 (1H, d, J=2.5 Hz, Ar—H), 6.66 (1H, d,J=2.3 Hz, Ar—H), 7.04 (1H, dd, J=8.5, 2.2 Hz, Ar—H), 7.22 (1H, d, J=2.2Hz, Ar—H ), 7.46 (1H, d, J=8.5 Hz, Ar—H)

[0297] Synthesis of7-Methylthio-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one(Compound of Example 1)

[0298] To 27.88 g (F.W.332.44, 1.13 mmol) of dimethoxy compound (47) wasadded 120 g of pyridine hydrochloride and stirred at 195° C. for 1.5hours with heating and then, ice water was slowly added thereto. Thereaction solution was extracted with ethyl acetate and the extract waswashed with 1N hydrochloric acid, water, a saturated sodium chlorideaqueous solution in the order named. After drying with anhydrousmagnesium sulfate, the extract thus obtained was concentrated. Theresidue was purified by silica gel column chromatography (developingsolvent; ethyl acetate:hexane=1:2). Furthermore, the residue wasrecrystallized from isopropyl alcohol-2-butanone to obtain 19.40 g (64%)of the title compound.

Example 2

[0299] Preparation of8-Methylthio-10,11-dihydrodibenzo[b,f]thiepin-1,3-diol (Compound ofExample 2)

[0300] In 50 mL of ethylene glycol was dissolved 665 mg (F.W. 332.43,2.0 mmol) of cyclized compound (47) and 2.9 mL (F.W. 50.06, d=1.032,60.0 mmol) of hydrazine monohydrate and 4.04 g (F.W. 56.11, 72.0 mmol)of potassium hydroxide were added thereto and stirred at 80° C. for 1.5hours. After raising the temperature to 140° C., the reaction solutionwas further stirred for five hours. Under cooling with ice, the reactionsolution was neutralized by addition of 1N hydrochloric acid. Thereaction solution thus neutralized was extracted with ethyl acetate andwashed with water and then with a saturated sodium chloride aqueoussolution. After drying with anhydrous sodium sulfate, the solvent wascompletely removed under reduced pressure to obtain a crude product. Theresidue was purified by silica gel column chromatography (developingsolvent: hexane:ethyl acetate=19:1) to obtain 238.5 mg (37.5%) of areduced compound (48).

[0301] To 238.5 mg (F.W. 318.45, 0.75 mmol) of reduced compound (48) wasadded 3.0 g of pyridine hydrochloride and stirred at 200° C. underheating for six hours and then, ice water was slowly added thereto, andthe resulting solution was extracted with ethyl acetate and the extractwas washed with 1N hydrochloric acid, water and a saturated sodiumchloride aqueous solution in the order named. After drying withanhydrous sodium sulfate, the obtained solution was concentrated. Theresidue was purified by silica gel column chromatography (developingsolvent;hexane:ethyl acetate=19:1) and further recrystallized fromhexane-ethyl acetate to obtain 132.7 mg (61%) of the title compound.

Example 3

[0302] Preparation of11-Diethyl-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one(Compound of Example 3)

[0303] To a suspension of 1.92 g (60% content, F.W. 24.00, 48.0 mmol) ofsodium hydride and 50 mL of tetrahydrofuran was added dropwise asolution of 5.72 g (F.W. 286.34, 20.0 mmol) of compound (49) dissolvedin 200 mL of tetrahydrofuran. The resulting suspension was stirred atroom temperature for 30 minutes and then, 3.84 mL (F.W. 155.97, d=1.94,48.0 mmol) of ethyl iodide was added thereto and further stirred at roomtemperature for two days. Under cooling with ice, ammonium chloride wasadded to the reaction solution and the tetrahydrofuran was completelyremoved under reduced pressure and then, the residue was partitionedwith ethyl acetate and water and washed with water and then with asaturated sodium chloride aqueous solution. After drying with anhydroussodium sulfate, the solvent was completely removed under reducedpressure to obtain 9.34 g of a crude product. The residue was purifiedby silica gel column chromatography (developing solvent; hexane:ethylacetate=9:1 to 3:1) to obtain 3.62 g of a mixture of compound (50) withcompound (51) and 2.62 g (F.W. 342.45, 7.65 mmol, 38.2%) of compound(52). The by-product of compound (52) was subjected to acid treatmentwith ethanol-concentrated hydrochloric acid to be converted to compound(51). With compound (51) the above described reaction was repeated to beled to compound (50).

[0304] The crude products (50) were combined and purified by silica gelcolumn chromatography (developing solvent; hexane:ethyl acetate=9:1 to5:1) to obtain 3.73 g (F.W. 342.45, 10.89 mmol, 54.5%) of compound (50).Demethylation reaction was carried out according to the method ofExample 1 to obtain the title compound.

Example 4

[0305] Preparation of11-Ethyl-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one (Compoundof Example 4)

[0306] To a suspension of potassium tert-butoxide (12.3 g, 110 mmol) and500 mL of tetrahydrofuran was added dropwise a solution of 30 g (F.W.286.34, 105 mmol) of compound (49) in 500 mL of tetrahydrofuran at 0° C.This suspension was stirred at room temperature for two hours and then,cooled to 0° C., and 16.8 mL (F.W. 155.97, d=1.94, 210 mmol) of ethyliodide was added thereto and stirred at room temperature for 20 hours.Under cooling with ice, hydrochloric acid was added to the reactionsolution, and tetrahydrofuran was completely removed under reducedpressure and then, the residue was partitioned with ethyl acetate andwater and the organic layer was washed with water and then with asaturated sodium chloride aqueous solution and dried with anhydrousmagnesium sulfate, and the solvent was removed under reduced pressure.The residue was purified by silica gel column chromatography (developingsolvent; hexane:ethyl acetate=4:1) and then, recrystallized frommethanol to obtain 18.7 g (yield 57%) of compound (51). Thedemethylation reaction of compound (51) was carried out according to themethod of Example 1 to obtain 14.8 g of the title compound.

Example 5

[0307] Preparation of3-(2-Thiophene)-7,9-dihydroxy-10,11-dihydrodibenz[b,f]oxepin-10-one(Compound of Example 5)

[0308] To 3-bromo-7,9-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one(27) (500 mg, 1.4 mmol), 2-(tributylstannyl)thiophene (0.9 mL, 2.8 mmol)and tetrakis(triphenylphosphine) palladium (82.5 mg, 0.07 mmol) wasadded 5 mL of hexamethylphosphoric triamide and stirred at 1001C for onehour. After completion of the reaction, the reaction solution waspartitioned with diethyl ether and water, and the organic layer waswashed with water and then with a saturated sodium chloride aqueoussolution and dried with anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (developing solvent; hexane:ethyl acetate=1:1)to obtain 538 mg (yield 89%) of3-(2-thiophene)-7,9-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one.Demethylation reaction was carried out according to the method ofExample 1 to obtain the title compound.

Example 6

[0309] Preparation of3-Phenyl-7,9-dihydroxy-10,11-dihydrodibenz[b,f]oxepin-10-one (Compoundof Example 6)

[0310] To 3-iodo-7,9-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one(52) (403 mg, 1.0 mmol), phenyl boronic acid (186 mg, 1.5 mmol), a 2Mpotassium carbonate aqueous solution (0.6 mL, 1.2 mmol) andtetrakis(triphenylphosphine) palladium (118 mg, 0.10 mmol) was added 5mL of toluene and stirred at 125° C. for 19 hours. After completion ofthe reaction, the reaction solution was neutralized with dilutehydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with water and then with a saturated sodium chloride aqueoussolution and dried with anhydrous magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (developing solvent; hexane:ethyl acetate=2:1)to obtain 108 mg (yield 31%) of3-phenyl-7,9-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one.Demethylation reaction was carried out according to the method ofExample 1 to obtain the title compound.

Example 7

[0311] Preparation of 7-Phenyl-10,11-dihydrodibenz[b,f]oxepin-1,3-diol(Compound of Example 7)

[0312] To 1,3-dimethoxy-7-bromo-10,11-dihydrodibenz[b,f]oxepin (53) (970mg, 2.9 mmol) obtained by reducing the 10-position of the carbonyl groupof the previous compound (27), phenylboronic acid (380 mg, 3.1 mmol),potassium carbonate (1.98 mg, 14.3 mmol), palladium acetate (20 mg, 0.09mmol) and tetra-n-butylammonium bromide (920 mg, 2.9 mmol) was added 5mL of water and stirred at 70° C. for one hour. After completion of thereaction, the reaction solution was neutralized with dilute hydrochloricacid and extracted with ethyl acetate. The organic layer was washed withwater and then with a saturated sodium chloride aqueous solution anddried with anhydrous magnesium sulfate, and the solvent distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (developing solvent;hexane:ethyl acetate=10:1) toquantitatively obtain 1.05 g of1,3-dimethoxy-7-phenyl-10,11-dihydrodibenz[b,f]oxepin. Demethylationreaction was carried out according to the method of Example 1 to obtainthe title compound.

Example 8

[0313] Preparation of3-Iodo-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one (Compoundof Example 8)

[0314] Synthesis of Carboxylic Acid (55)

[0315] A mixture of 14.1 g (F.W. 282.46, 50.0 mmol) of2-chloro-3-iodobenzoic acid (54), 8.46 g (F.W. 338.44, 25.0 mmol) ofdisulfide (9), 1.58 g (F.W. 63.55, 25.0 mmol) of copper (powder), 4.76 g(F.W. 190.45, 25.0 mmol) of copper (I) iodide, 12.4 g (F.W. 138.21, 90.0mmol) of potassium carbonate and 100 mL of N-methyl-2-pyrrolidone wasstirred at 120° C. for 1.5 hours. This reaction solution was cooled bystanding, and made pH 2 with 4N hydrochloric acid. The resultingsolution was extracted with ethyl acetate and washed with water and asaturated sodium chloride aqueous solution in the order named. Afterdrying with anhydrous sodium sulfate, the solvent was removed underreduced pressure, and the resulting crude carboxylic acid wasrecrystallized from ethyl acetate to obtain 4.21 g (F.W. 416.23, 10.1mmol) of carboxylic acid (55). The filtrate after recrystallization wasfurther crystallized (from ethyl acetate) to obtain 3.45 g (F.W. 416.23,8.3 mmol) of carboxylic acid (55). The yield was 36.8%.

[0316] Synthesis of Alcohol (56)

[0317] To a solution of 7.66 g (F.W. 416.23, 18.4 mmol) of carboxylicacid (55) in 20 mL of tetrahydrofuran was added 722 mg of sodiumborohydride and then, 2.74 mL of boron trifluoride diethyl etherate wasadded dropwise thereto. The resulting mixture was stirred at roomtemperature for 45 minutes. Ice water was slowly added to this reactionsolution. The reaction solution thus obtained was extracted with ethylacetate and washed with a saturated sodium chloride aqueous solution.After drying with anhydrous magnesium sulfate, the solvent was removedunder reduced pressure. The resulting crude product was purified bycolumn chromatography (developing solvent; hexane:ethyl acetate=4:1) toquantitatively obtain 7.59 g (F.W. 402.25) of alcohol (56).

[0318] Synthesis of Bromide Compound (57)

[0319] To a solution of 7.49 g (F.W. 402.25) of crude alcohol (56) in 20mL of methylene chloride was added 0.62 mL of phosphorus tribromide at0° C. and stirred at room temperature for 30 minutes. To this reactionsolution was added slowly ice water. The reaction solution was furtherstirred at room temperature for 30 minutes and then, extracted withmethylene chloride and the extract was washed with water and then with asaturated sodium chloride aqueous solution. After drying with anhydrousmagnesium sulfate, the solvent was removed under reduced pressure. As aresult, a crude product was obtained. This crude product was purified bysilica gel column chromatography (developing solvent; hexane:ethylacetate=4:1) to obtain 5.14 g (F.W. 465.14, 11.05 mmol) of bromide (57).The yield was 61.4% in two steps.

[0320] Synthesis of Nitrile Compound (58)

[0321] In 20 mL of dimethyl sulfoxide was dissolved 5.00 g (F.W. 465.14,10.75 mmol) of bromide (57). To this solution was added 630 mg of sodiumcyanide and stirred at 80° C. for one hour. Under cooling with ice, tothe resulting solution was added water and then, the obtained solutionwas extracted with ethyl acetate, and the extract was washed with waterand a saturated sodium chloride aqueous solution in the order named.After drying with anhydrous magnesium sulfate, the solvent was removedunder reduced pressure and the crude product thus obtained was purifiedby silica gel column chromatography (developing solvent; hexane:ethylacetate=3:1) to obtain 2.30 g (F.W. 411.26, 5.59 mmol) of nitrilecompound (58) and 2.06 g (F.W. 411.26) of crude nitrile compound (58).

[0322] Synthesis of Carboxylic Acid (59)

[0323] To 30 ml of ethanol 2.27 g (F.W. 411.26, 5.5 mmol) of nirilecompound (58) was added and completely dissolved by raising thetemperature to 110° C. To this solution was added 2.35 mL of a 1N sodiumhydroxide aqueous solution. The resulting solution was further stirredat 110° C. overnight. To the reaction solution was added ice and theobtained solution was neutralized with 1N hydrochloric acid. Theresulting solution was extracted with ethyl acetate and the extract waswashed with water and then with a saturated sodium chloride aqueoussolution. After drying with anhydrous magnesium sulfate, the solvent wascompletely removed under reduced pressure to obtain 2.36 g (F.W. 430.26)of crude carboxylic acid (59).

[0324] Synthesis of Cyclized Compound (60)

[0325] To 4.40 g (F.W. 430.26 mmol) of crude carboxylic acid (59) wasadded 60 mL of methanesulfonic acid to dissolve crude carboxylic acid(59). The resulting solution was stirred at room temperature overnight.To the reaction solution was added water under cooling with ice andthen, the resulting solution was extracted with ethyl acetate and theextract was washed with water and then with a saturated sodium chlorideaqueous solution. After drying with anhydrous magnesium sulfate, thesolvent was completely removed to obtain a crude product which was thenpurified by silica gel column chromatography (developing solvent;hexane:ethyl acetate=4:1). Furthermore, recrystallization of the productthus obtained was repeated from hexane and methylene chloride and fromhexane and ethyl acetate to obtain 1.82 g (F.W. 412.24, 4.4 mmol) ofcyclized compound (60). The yield was 41.1% in three steps.

[0326] Synthesis of3-Iodo-7.9-dihydroxy-10,11-dihydrodibenzo[b.f]thiepin-10-one (Compoundof Example 8)

[0327] To 412.2 mg (F.W. 412.24, 1.0 mmol) was added 2.0 g of pyridinehydrochloride and the temperature was raised up to 200° C. The resultingsolution was stirred at 200° C. for two hours and then, ice water wasslowly added thereto. The reaction solution thus obtained was extractedwith ethyl acetate to which a small amount of tetrahydrofuran had beenadded and the extract was washed with 1N hydrochloric acid, water and asaturated sodium chloride aqueous solution in the order named. Afterdrying with anhydrous magnesium sulfate, the solvent was completelyremoved under reduced pressure to obtain 289.1 mg of a crude product.This crude product was purified by silica gel column chromatography(developing solvent; hexane:ethyl acetate=9:1 to 4:1). Furthermore, theproduct thus obtained was recrystallized from chloroform to obtain 150.1mg (F.W. 384.19, 39.1 mmol) of the title compound. The yield was 39.1%.

Example 9

[0328] Preparation of3-Bromo-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one (Compoundof Example 9)

[0329] Synthesis of Carboxylic Acid (61)

[0330] A mixed solution of 58.87 mg (F.W. 235.47, 0.25 mmol) of3-bromo-2-chlorobenzoic acid (3), 42.31 mg (F.W. 338.44, 0.10 mmol) ofdisulfide (80%) (9), 7.94 mg (F.W. 63.55, 0.125 mmol) of copper(powder), 23.81 mg (F.W. 190.45, 0.125 mmol) of copper (I) iodide, 41.46mg (F.W. 138.21, 0.30 mmol) of potassium carbonate and 3 mL ofN-methyl-2-pyrrolidone was stirred at 150° C. for 2.5 hours. Thisreaction solution was cooled by standing, and made pH 2 with 1Nhydrochloric acid. The resulting solution was extracted with ethylacetate and washed with water and a saturated sodium chloride aqueoussolution in the order named. After drying with anhydrous sodium sulfate,the solvent was removed under reduced pressure to give crude carboxylicacid (61) (F.W. 369.23). The yield was 64.5% by HPLC.

[0331] The procedure after the synthesis of carboxylic acid (61) wascarried out according to the method of Example 8 to obtain the titlecompound.

Example 10

[0332] Preparation of8-Propionyl-10,11-dihydrodibenz[b,f]oxepin-1,3-diol (Compound of Example10)

[0333] To a suspension of aluminum chloride (1 g, 7.5 mmol) in anhydrousmethylene chloride (3 mL) was added propionyl chloride (668 FL, 7.7mmol) and stirred at room temperature for one hour. This solution wasadded dropwise to a solution of 10,11-dihydrodibenz[b,f]oxepin-1,3-dioldiacetate (62) (300 mg, 0.96 mmol) in methylene chloride (5 mL) at 0° C.and stirred at room temperature for one hour. To the reaction solutionwas added dropwise methanol (10 mL) at 0° C. and a 20% sodium hydroxideaqueous solution (3 mL) was added thereto and stirred at roomtemperature for 30 minutes. After completion of the reaction, thereaction solution was poured into hydrochloric acid-ice water andextracted with ethyl acetate, and the organic layer was washed withwater and then with a saturated sodium chloride aqueous solution anddried with anhydrous magnesium sulfate and the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (developing solvent; hexane:ethyl acetate=2:1), andrecrystallization was carried out from ethyl acetate and hexane toobtain 190 mg (yield 70%) of skin-colored needles of the title compound.

Example 11

[0334] Preparation of8-(1-Hydroxyiminoethyl)-10,11-dihydrodibenzo[b,f]thiepin-1,3-diol(Compound of Example

[0335] In ethanol, 180 mg of8-acetyl-10,11-dihydrodibenzo[b,f]thiepin-1,3-diol (63) was dissolved,and an aqueous solution of 49 mg of hydroxylamine hydrochloride and 100mg of sodium acetate dissolved in 1 mL of water was added thereto. Themixed solution was stirred at 120° C. for 3 hours, concentrated underreduced pressure and then, extracted with ethyl acetate. The organiclayer was washed with water and a saturated sodium chloride solution andthen, dried with anhydrous magnesium sulfate and the solvent wasdistilled off under reduced pressure. The residue was purified by silicagel column chromatography (developing solvent; hexane:ethylacetate=1:1). Upon recrystallization from chloroform-hexane, 120 mg ofskin-colored amorphous title compound was obtained (yield 63%). MeltingPoint: 215.4 to 217.5° C.

Example 12

[0336] Preparation of 8-Hexyl-10,11-dihydrodibenz[b,f]oxepin-1,3-diol(Compound of Example 12)

[0337] In a pressure reaction vessel, 200 mg of2-bromo-7,9-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one (64), 32 mgof a palladium complex, 34 mg of triphenylphosphine and further 11.8 mgof copper iodide were charged and 3 mL of acetonitrile (dehydrated) wasadded thereto and stirred. To this solutionO,N-bis(trimethylsilyl)acetamide (hereinafter referred to as “BSA”) wasadded at room temperature and stirred for 5 minutes to effectsilylation. After silylation, 110 FL of 1-hexyne and 250 FL ofN,N-diisopropylethylamine were added and the vessel was heat sealed, andstirred at 120° C. under heating for 17 hours. After completion of thereaction, the reaction solution was partitioned with ethyl acetate anddilute hydrochloric acid. The organic layer was washed with water and asaturated sodium chloride solution and then, dried with anhydrousmagnesium sulfate and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(developing solvent; hexane:ethyl acetate=3:1). To the obtained oilysubstance was added 5 mL of ethyl acetate to dissolve the oily substanceand 20 mg of palladium-carbon was added thereto to effect hydrogenationovernight. After completion of the reaction, the reaction solution wasfiltered, concentrated and the residue as purified by silica gel columnchromatography (developing sovent; hexane:ethyl acetate=7:1). Uponrecrystallization from chloroform-hexane, 49.3 mg of colorless plates ofthe title compound was obtained (yield 24.3%).

[0338] Various compounds of the present invention were synthesized inthe same manner as in each of the above described Examples. Thestructures of a total of 178 compounds synthesized including thecompounds synthesized in Examples 1 to 12, and the compounds of Examplesused in the following Experimental Examples are collectively shownbelow. These compounds can be prepared by combinations of {circle over(1)}: Ullmann reaction; {circle over (2)}-1: Friedel-Crafts reaction or{circle over (2)}-2: photoreaction; {circle over (3)}: carbon atomincreasing reaction; {circle over (4)}: conversion reaction of ahalogens to another functional group; {circle over (5)}: introductionreaction of an alkyl group or an alkylcarbonyl group; {circle over (6)}:conversion reaction at 10-position; and {circle over (7)}: reaction ofDeprotection according to the same methods as the preparation methods ofReferential Examples and Examples, and the preparation steps of eachcompound will be explained in Table 1.

[0339] Further, the data of the properties of these compounds are listedin Table 2 to Table 18. TABLE 1 Example Nos. Preparation Steps Examples13 to 23 {circle over (1)}→{circle over (2)}-1→{circle over (3)}→{circleover (7)} Examples 24 to 36 {circle over (1)}→{circle over(2)}-1→{circle over (3)}→{circle over (6)}→{circle over (7)} Examples 37to 46 {circle over (1)}→{circle over (2)}-1→{circle over (3)}→{circleover (5)}→{circle over (7)} Examples 47 to 101 {circle over (1)}→{circleover (2)}-1→{circle over (3)}→{circle over (4)}→{circle over (7)}Examples 102 to 127 {circle over (1)}→{circle over (2)}-1→{circle over(3)}→{circle over (4)}→{circle over (6)}→{circle over (7)} Examples 128to 151 {circle over (1)}→{circle over (2)}-1→{circle over (3)}→{circleover (5)}→{circle over (6)}→{circle over (7)} Example 4, Example 37,{circle over (1)}→{circle over (2)}-2→{circle over (5)}→{circle over(7)} Example 152 Examples 153 to 163, {circle over (1)}→{circle over(2)}-1→{circle over (3)}→{circle over (4)}→{circle over (5)}→{circleover (7)} Examples 169 to 179 Example 1

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Comparative example

[0340] TABLE 2 Example melting point NMR Appear- No (centi degree) NMRsolvent IR ance Mass UV 1 189.4-191.9 2.47(3 H, s, CH3) · 4.03(2 H, s,CH2) · DMSO-d6 3213- 332-285 λ max nm (ε) · 243 5.86(1 H, s, OH) ·6.15(1 H, d, J = 1611 (23100) · 278 2.5 Hz, Ar—H) · (27600) · 345.66.35(1 H, d, J = 2.5 Hz, Ar—H) · (7900) · 7.15(1 H, s, Ar—H) · 7.20(2 H,d, J = 7.8 Hz Ar—H) · 12.96(1 H, s, OH) 2 161.6-163.9 2.97-3.00(2 H, m,CH2) · 3.27- DMSO-d6 3463- ε max 20209 (λ 3.30(2 H, m, CH2) · 3368- max283.6 nm) · ε 6.28(1 H, d, J = 2 Hz, Ar—H) · 1606 max 17842 (λ max6.33(1 H, d, J = 2 Hz, Ar— 259.6 nm) H) · 7.08(1 H, dd, J = 8.2 Hz,Ar—H) · 7.23(1 H, s Ar— H) · 7.40(1 H, d, J = 8 Hz, Ar— H) · 7.62(1 H,s, Ar—H) · 9.28(1 H, brs, OH) · 9.49(1 H, brs, OH) 3 238.0-244.1 0.74(6H, t, J = 7 Hz, CH3) · DMSO-d6 3467- needle 314 ε max 15545 (λ max2.08(1 H, q, J = 7 Hz, CH2) 3267- crystal (M+, base) 260.8 nm) · ε max2.11(1 H, q, J = 7 Hz, CH2) 2973- 20821 (λ max 2.36(1 H, q, J = 7 Hz,CH2) 2963- 244 nm) 2.49(1 H, q, J = 7 Hz, CH2) · 2957- 6.83(1 H, s,Ar—H) 2934- 6.90(1 H, s, Ar—H) · 7.27(1 H, 2875- t, J = 7 Hz, Ar—H) ·1646- 7.44(1 H, t, J = 7 Hz, Ar—H) · 1596- 7.53(1 H, d, J = 7 Hz, Ar—1508- H) 7.64(1 H, d, J = 7 Hz, Ar—H) · 1451- 9.68(2H 4 237.8- 0.90(3 H,t, J = 7.2 Hz, CH3) · DMSO-d6 3503- pinkish- 286(M+, ε max 6018 (λ 239.41.91-1.99(1 H, m, J = 3281- white Base)-271- max 338.4 nm) · ε (decom-7.7 Hz, CH2) · 2.35- 2970- needle 257-229 max 22356 ( λ max position)2.68(1 H, m, J = 7.7 Hz, CH2) · 1644- crystal 257.2 nm) · ε max 4.61(1H, t, J = 7.1 Hz, CH) · 1596- 23553 (λ max 6.96(1 H, s, Ar—H) ·  784243.2 nm) 7.230H, t, J = 7.6 Hz, Ar—H) · 7.35(1 H, d, J = 7.6 Hz, Ar—H)· 7.47(1 H, t, J = 7.7 Hz, Ar—H) · 7.49(1 H, s, Ar—H)- 7.70(1 H,d, J =7.6 Hz, Ar—H) · 5 227.6-228.1 4.18(2 H, s, CH2) · 6.16(1 H, d, J =DMSO-d6 3340- pale 324(M+, Base) ε max 28742.1 (λ 2.4 Hz Ar—H) · 1633-yellow max 281.0 nm)- 6.50(1 H, d, J = 2.4 Hz, Ar—H) · 1610- needle7.20(1 H, t, J = 4.3 Hz, Ar—H) ·  704- crystal 7.51-7.71(5 H, m, Ar— H)· 11.11(1 H, brs, OH) · 1307(1 H, s, OH). 6 182.7-1844 4.21(2 H, s, CH2)· 6.16(1 H, d, J = DMSO-d6 3339- pale mud 318(M+, Base) ε max 7353 (λ2.4 Hz, Ar—H) · 1614- yellow max 321.6 nm) · ε 6.50H, d, J = 2.5 Hz,Ar—H) · 1586 needle max 15358 (λ max 7.43(8 H, m, Ar—H)- crystal 286.2nm) · ε max 11.10(1 H, brs, OH) · 13.08(1 H, 5, OH) 21057 (λ max 256.8nm) 7 179.6-180.4 2.85-2.86(2 H, m, CH2) · 3.09- 3440- pale pink 304(M+,Base) λ max nm (ε) · 3.12(2 H, m, CH2) · 3368- plate crystal 207.6(64200) · 247.8 6.18(1 H, d, J = 2.4 Hz, Ar—H) · 2923- (sh 24300) 6.19(1 H, d, J = 2.4 Hz, Ar—H) · 2854- 7.35-7.53(6 H, m, Ar—H) · 1624-7.70- 7.72(2 H, m, Ar—H) · 1610- 9.25(1 H, br, OH) · 9.44(1 H, br, OH) ·1509- 1457 8 >250 4.36(2 H, s, CH2) · 6.26(1 H, d,J = DMSO-d6 3330- 384ε max 8579.4 (λ (decom- 2 Hz, Ar—H) · 1618 (M+, base)- max 343.0 nm) · εposition) 6.70(1 H, d, J = 2 Hz, Ar—H) · 351 (M +− max 12476.8 (λ max7.37(1 H, d, J = 8 Hz, Ar— 33)-257 301.2 nm) · ε max H) · 7.84(1 H, dd,J = 8,1 Hz, (M +− 127) 31556.5 (λ max Ar—H) · 8.08(1 H, d, J = 1 Hz,240.4 nm) · ε max Ar—H) · 11.10(1 H, brs, OH) · 49370 (λ max 13.48(1 H,s, OH) 203.0 nm) 9 >200 4.3 1 (2 H,s, CH2) · 6.19(1 H, d, J = DMSO-d63338- white 338(M+, ε max 7008 (λ subli- 2.3 Hz, Res-H) · 1599 needleBase)-336 · max 340.0 nm) mation 6.63(1 H, d, J = 2.3 Hz, Res-H)-crystal 305-303- ε max 10843 (λ max and 7.46(1 H, d, J = 8 Hz, Ar—H) ·257- 301.6 nm) decom- 7.61(1 H, dd, J = 8,2 Hz, Ar—H) · ε max 9218 (λposition) 7.86(1 H, d, J = 2, Ar— max 278.4 nm) H) · 11(1 H, brs, OH) ·ε max 21932 (λ max 13.40(1 H, s, OH) 238.8 nm) 10 159.0-160.3 1.05(3 H,t, J = 7 Hz, CH3) · DMSO-d6 3361- pinkish 284(M+)- ε max 12965 (λ max2.79(2 H, m, CH2) · 2.98(2 H, q, 3197- white 269- 260.8 nm) · J = 7 Hz,CH2) · 3.06(2 H, m, CH2) · 2944- needle 255(Base) ε max 12364(λ 6.07(1H, d, J = 2.5 Hz, Ar—H) · 1660- crystal max 6.11(1 H, d, J = 2.5 Hz,Ar—H) · 1621- 245.6 nm) · 7.18(1 H, d, J = 8 Hz, Ar—H) · 1598 ε max51685U 7.78(1 H, dd, J = 2.8 Hz, Ar—H) · max 207.2 nm) 7.83(1 H, d, J =2 Hz, Ar—H) · 9.26(1 H, br, OH) · 9.41(1 H, br, OH) 11 215.4-217.52.11(3 H, s, CH3) · 2.96(2 H, m, CH2) · DMSO-d6 3361- pinkish 301(M+, εmax 11366(λ max 3.23(2 H, m, CH2) · 6.23(1 H, d, J = 2938- whiteBase)-284 291.6 nm) · 2.4 Hz, Ar—H) · 6.28(1 H, d, J = 1607 amorphous εmax 10157(λ 2.4 Hz, Ar—H) · 7.39(2 H, m, Ar—H) · max 7.51(1 H, m, Ar—H)· 273.2 nm) · 9.20(1 H, brs, OH) · ε max 43942(λ 9.43(1 H, brs, OH) ·max 211.6 nm) 11.20(1 H, brs, OH)

[0341] TABLE 3 Example melting point NMR No (centi degree) NMR solventIR Appearance Mass UV 12 109.5-111.2 0.820(3 H, t, J = 6.4 Hz, −CH3) ·DMSO-d6 3316- colorless ε max 6755 (λ max 1.23-1.26(6 H, m, CH2 * 3) ·2959- plate crystal 327.6 nm) · 1.507(2 H, t, J = 7.0 Hz, CH2) · 2924- emax 6396( λ max 2.521(2 H, t, J = 7.5 Hz, CH2) · 2856- 312.8 nm) ·4.040(2 H, s, CH2) · 6.060(1 H, d, J = 1636- ε max 13808 (λ max 2.3 Hz,Ar—H) · 6.333(1 H, d, J = 1593- 287.2 nm) · e max 2.3 Hz, Ar—H) ·7.089(1 H, dd, 1497- 4863 (λ max 255.6 nm) J = 8.0,1.3 Hz, Ar—H) ·7.16-1445 7.21(2 H, m, Ar—H) · 10.970(1 H, s, Ph—OH) · 12.997(1 H, s, Ph—OH)13 236.4-237.3 4.34(2 H, s, CH2) · 6.17(1 H, d, J = DMSO-d6 3339- paleyellow 336 λ max nm (ε) · 2.3 Hz, Res-H) · 6.62(1 H, d, J = 1618- needle(M+, base)- 206.4 (46400) · 38.5 2.3 Hz, Res-H) · 7.47(1 H, d, J = 1602crystal 303 (M +− (27700) · 272.4 8.3 Hz, Ar—H) · 7.59(1 H, d, J =33)-257 (13900) · 300.4 8.3 Ar—H) · 7.77(1 H, s Ar—H) · (M +− 79)(12600) · 340.0 (8800) 10.99(1 H, s, OH) · 13.37(1 H, s, OH) 14 187.53.90(3 H, s, CH3) · 4.46(2 H, m, CH2) · DMSO-d6 3448- white needle 352 λmax nm (ε) · (subli- 6.51(1 H, d, J = 2 Hz, Ar—H) · 1612- crystal (M ++2.base)- 2064 (44800) · 239.2 mation) 6.85(1 H,d,J = 2 Hz, Ar— 1576 350(M+)- (25900) · 2707 H) · 7.58(1 H,d, J = 8 Hz, Ar—H) · 317 (M +−(14100) · 298.8 7.69(1 H, d, J = 8 Hz, Ar—H) · 33)-271 (11300) · 340.0(6200) 7.89(1 H, s, Ar—H) · (M +− 79) 13.50(1 H, s, Ph—OH) ·· 15217.9-221.6 4.43(2 H, s, CH2) · 6.26(1 H, d, J = DMSO-d6 3338- needle292 λ max nm (ε) · 2 Hz, Ar—H) · 6.71(1 H, d, J = 3089- crystal (M+,base)- 203.6 (53600) · 269.6 2 Hz, Ar—H) · 7.43(1 H, dd, J = 1602 white259 (M +− (14900) · 300.8 8.2 Hz, Ar—H) · 33)- (13100) · 340.0 7.73(1 H,d, J = 2 Hz, Ar—H) · (9100) · 7.75(1 H,d, J = 8 Hz, Ar— H) · 11.09(1 H,brs, OH) · 13.46(1 H, s, OH) · 16 4.12(2 H, s, CH2) · 6.26(1 H, d, J =DMSO-d6 3368- λ max nm (ε) · 2 Hz, Ar—H) · 3227- 287.6 (7500) · 326.46.71(1 H, d, J = 2 Hz, Ar—H) · 1634- (5500) · 7.43-7.75(3 H, d, J = 8Hz, 1615- Ar—H) · 1 1.09(1 H, brs, OH) · 1498 12.94(1 H, s, OH) 17 >2004.60(2 H, s, CH2) · 6.27(1 H, d, J = DMSO-d6 3362- ε max 8119 (λ max(decom- 2 Hz, Ar—H) · 6.72(1 H, d, J = 1617- 340.0 nm) · ε max position)2 Hz, Ar—H) · 7.36(1 H, t, J = 1595 12239 (λ max 8 Hz, Ar—H) · 7.64(1 H,d, J = 299.2 nm) · ε max 8 Hz, Ar—H) · 7.73(1 H, d, J = 23541 (λ max 8Hz, Ar—H) · 11.11(1 H, brs, OH) · 240.8 nm) · ε max 13.42(1 H, s, OH) ·47654 (λ max 205.2 nm) 18 245.3-246.6 2.47(3 H, s, CH3) · 4.03(2 H, s,CH2) · DMSO-d6 3168- needle 320 (M+) λ max nm (ε) · 5.86(1 H, s, OH) ·6.15(1 H, d, J = 1610- crystal 203.6 (59600) · 286.8 2.5 Hz, Ar—H) ·6.35(1 H, d, J = 1578 (18800) · 340.0 2.5 Hz, Ar—H) · 7.1 5(1 H,s Ar—H)· (13600) · 7.20(2 H, d, J = 7.8 Hz .Ar—H) · 12.96(1 H, s, OH) 19182.3-184.4 2.48(3 H, s, CH3) · 4.27(2 H,s, CH2) · DMSO-d6 3333- needle304(M+, λ max nm (ε) · 6.18(1 H, d, J = 2.4 Hz, Ar—H) · 1594 crystalBase)-271- 245.2 (23900) · 258.4 6.63(1 H, d, J = 2.3 Hz, Ar—H) · 257-(24100) · 298.4 7.30(1 H,d, J = 8.0 Hz, Ar—H) · (12400) · 340.0 7.42(1H, d, J = 8.0 Hz, Ar—H) (9400) 7.51(1 H,s, Ar—H) · 10.9(1 H, br, OH) ·13.45(1 H, s, OH) 20 >250 4.23 (2 H, s, CH2) · 6.97 (1 H, s, DMSO-d63453- pale brown 336(M+, ε max 15804 (λ max Ar—H) · 7.43(1 H, d, J =3261- needle Base)-336 259.6 nm) · ε max 8.1 Hz, Ar—H) · 1647- crystal21547 (λ max 7.51 (1 H, s, Ar—H) · 1602- 240.4 nm) · ε max 7.59(1 H, dd,J = 8.1-1.8 Hz, 1589- 34053 (λ max Ar—H) · 7.88(1 H, d, J = 1.6 Hz,1512- 206.0 nm) Ar—H) · (2 H, brs, OH) 1465 21 2.44(3 H, s, CH3) ·4.16(2 H, s, CH2) · DMSO-d6 3542- 304(M+)-257 λ max nm (ε) · 6.96(1 H,Ar—H) · 3344- (M +− SMe) 205.6 (28400) · 249 6 7.25(1 H, m, Ar—H) ·1638- (23400) · 264.4 7.36(1 H, d, J = 8 Hz, Ar—H) · 1591- (25900) ·282.4 7.48(2 H, 8.Ar—H) 1506 (25200) · 337.6 (4900) 22 285.7 4.23(2 H,s,CH2) · DMSO-d6 3452- plate crystal 33B(M+, λ max nm (ε) · (decom- 6.95(1H, s, Ar—H) · 3246- Base)-336- 246.8 (28400) · 283.3 position) 7.41(1 H,dd, J = 8.2 Hz, Ar—H) 1652- 305-303- (15300) · 337.6 7.48(1 H, s, Ar—H)· 7.58(1 H, d, 1604 257- (6300) J = 8 Hz, Ar—H) · 7.70(1 H, d, J = 2 Hz,Ar—H) · (2 H, brs, OH) 23 232.0-236.9 2.45(3 H, s, CH3) · DMSO-d6 3457-needle 304(M+)- λ max nm (ε)- 4.20(1 H, s, CH2) · 3239- crystal 257(M +−203.6 (36000) · 248.0 6.94(1 H, s, Ar—H) · 1647- SMe) (29300) · 260.47.10(1 H, dd, J = 1603- (29700) · 335.6 7.2.1 Hz, Ar—H) · (6800) 7.32(1H, d, J = 1.0 Hz, Ar—H) · 7.48(1 H, s, Ar— H) ·7.55(1 H, d, J = 8.2 Hz,Ar—H) ·

[0342] TABLE 4 Example melting point NMR Appear- No (centi degree) NMRsolvent IR ance Mass UV 24 208.0-213.7 4.20(2 H, s, CH2) · 6.06(1 H, d,J = DMSO-d6 3390- colorless 257(M+, ε max 13691 3 Hz, Ar—H) · 6.29(1 H,d, J = 3339- needle Base)-211 (λ max 3 Hz, Ar—H) · 7.16(1 H, ddd, J =3223- crystal 273 6 nm) · 7,7,2 Hz, Ar—H) · 7.23(1 H,dd, J =   1618-1599ε max 7,2 Hz, Ar—H) · 7662 (λ max 7.27(1 H, ddd, J = 7,7,2 Hz, Ar—H) ·253.2 nm) · 7.34(1 H, d, J = 7.2 Hz, Ar—H) · ε max 10.01(1 H, br, OH) ·11.53(1 H, br, OH) · 32958 (λ 12.25(1 H, brs, OH) max 205.2 nm) 254.02(3 H, s, CH3) · 4.26(2 H, s, CH2) · DMSO-d6  3352(OH)-    pinkish27l(M+, ε max 15241 6.16(1 H, d, J = 2 Hz, Ar—H) ·  2935(CH)-     whitebase)-211 (λ max 6.39(1 H, d, J = 2 Hz, Ar—  1634(CN)-     needle 283.6nm) · H) · 7.22-7.41(4 H, m, Ar—H) · 1597 crystal ε max 10.21(1 H, br,OH) · (aroma) 7228 (λ max 11.63(1 H, brs, OH) 255.2 nm) · ε max 3726 (λmax 204.4 nm) 26 181.1-184.9 2.98-3.01(2 H, m, CH2) · 3.28- DMSO-d63429- 278 ε max 11694 3.11(2 H, m, CH2) ·   3370-1608 (M+, (λ max 6.30(1H,d,J = 2 Hz, Ar—H) · base)- 276.8 nm) · 6.35(1 H, d, J = 2 Hz, Ar—H) ·263 (M +− ε max 7.25(1 H, dd, J = 8,2 Hz, Ar—H) · 155-245 58928 (λ max7.43(1 H, d, J = 2 Hz, Ar—H) · (M +− 202.0 nm) 7.48(1 H, d, J = 8 Hz,Ar— 33)-210 H) · 9.31(1 H, s, OH) · 9.55(1 H, s, OH) (M +− 68) 27127.3-130.7 3.03-3.06(2 H, m, CH2) · DMSO-d6 3368- 278 ε max 88813.42-3.45(2 H, m, CH2) · 1593- (M+, (λ max 275.2 6.32(1 H, d, J = 2 Hz,Ar—H) · base)- nm) · ε 6.36(1 H, d, J = 2 Hz, Ar— 263 (M +− max 55704 H)· 7.21(1 H, t, J = 8 Hz, Ar—H) · 15)-245 (λ max 7.48(2 H, t, J = 8 Hz,Ar—H) · (M +− 204.4 nm) 9.35(1 H, brs, OH)- 33)-243 9.57(1Hirs, OH) (M+− 35)-210 (M +− 68) 28 182.9-184.4 2.45(3 H, s, CH3) · 6.30(1 H, d, J =3340- plate 288(M+, λ max nm 1.9 Hz, Ar—H) ·   1599-1575 crystal Base)-(ε) · 6.33(1 H, d, J = 1.8 Hz, Ar—H) · 256-241 239.6 (29100) · 6.79(1 H,d, J = 12.4 Hz, CH—H) 276.4 7.05(1 H, d, J = 12.4HZ, CH—H) · (26000) ·3264 7.20(2 H, m, J = 5.2 Hz, Ar—H) · (8300) 7.29(1 H, d, J = 3.6 Hz,Ar—H) 9.66(1 H, s, OH) 9.83(1 H, s, OH) · 29 237.4-238.6 3.04-3.07(2 H,m, CH2) · DMSO-d6 3394- white 269 λ max nm 3.27-3.30(2 H, m, CH2) ·2229- needle (M+, (ε) · 6.33(1 H, d, J = 2 Hz, Ar—H) · 1613- crystalbase)- 206.0 (49700) · 6.37(1 H, d, J = 2 Hz, Ar—   1499-1454 254 (M+-299.6 H) · 7.64(2 H, s, Ar—H) · 15)-236 (11400) 7.78(1 H, s, Ar—H) · (M+− 33) 9.33(1 H, s, OH) 9.57(1 H, s, OH) 30 0.95(3 H, t, J = 7.3 Hz,CH3) · DMSO-d6 3386- pale yellow 302(M+)- ε max 6083 1.99-2.05(1 H, m,CH2) · 3082- needle 226 (Base) (λ max 2.32-2.37(1 H, m, CH2) ·  1671-1586 crystal 321.6 nm) · ε 4.31(1 H, t, J = 6.76 Hz, CH) · max32503 7.21-7.26(1 H, m, Ar— (λ max H) · 7.31(1 H, s, Ar—H) · 244.4 nm) ·7.45-7.52(4 H, m, Ar—H) · ε max 7.63(1 H, m, Ar—H) 37486 (λ max 210.4nm) ·· 31 194.2-196.1 1.67(6 H, s, CH3) · DMSO-d6 3470- orange 285(M+)-ε max 3969 6.8(1 H, s, Ar—H) · 3337- pnsm 272 (Base) (λ max 339.2 7.10(1H, s, Ar—H) ·   1633-1595 nm) · ε 7.24(1 H, t, J = 1 Hz, Ar—H) · max20771 7.54(1 H, t, J = 1.1 Hz, Ar—H) · (λ max 7.59(2 H, dd, J = 8, 260.0nm) 1.3 Hz, Ar—H) ·· ε max 21.049 (λ max 242.0 nm) · ε max 35595 (λ max204.4 nm) · 32 1.01(3 H, t, J = 7.2 Hz, CH3) · DMSO-d6 3339- needle 332-λ max nm 2.02-2.09(1 H, m, CH2) · 2968- crystal 303-285 (ε) ·2.50-2.58(1 H, m, CH2) · 2917- 204.4 (33400) · 4.73(1 H, dd, J = 8.2,6.0 Hz, CH) · 2878- 246.0 5.45(1 H, s, OH) · 6.8(1 H, dd, J =  1621-1590 (22300) · 8.8, 2.5 Hz, Ar—H) · 272.8 (sh 7.04(1 H, m, Ar—16300) · H) · 7.16(1 H, t, J = 295.2 4.4 Hz, Ar—H) · (11200) · 7.36(1 H,d, J = 6.8 Hz, 340.0 Ar—H) · 7.40(1 H, dd J = (6900) 7.2.1 Hz, Ar—H) ·7.64(1 H, dd, J = 8.8, 1.0 Hz, Ar—H) ·8.1 33 2.83(2 H, t, J = 6 Hz, CH2)· DMSO-d6 3524- 2S7 λ max nm 3.07(2 H, t, J = 6 Hz, CH2) · 3298- (M+,(ε) · 4.01(2 H, s, NCH2) · 3156- base)- 206.4 (45100) · 6.12(1 H, d, J =2 Hz, Ar—H) · 2999- 240 (M +− 274.0 6.18(1 H, d, J = 2 Hz, Ar—H) · 2897-17) (3400) 7.19(1 H, d, J = 8 Hz, Ar—H) · 1624- 7.33(1 H, d, J = 8 Hz,Ar—H) · 1605- 7.39(1 H, s, Ar—H) · 1509- 9.29(1 H, s, OH) 9.43(1 H, s,OH)   1496-1458 34 2.99(2 H, t, J = 6 Hz, CH2) · DMSO-d6 3433- 273 λ maxnm 3.28(2 H, t, J = 6 Hz, CH2) · 1595- (M+, (ε) · 3.72(2 H, s, NCH2) ·1560- base)- 204.8 (41200) · 6.27(1 H, d, J = 2 Hz, Ar—H) · 1457- 256 (M+− 275.6 6.34(1 H, d, J = 2 Hz, Ar— 17)-223 (8400) H) · 7.15(1 H, d, J =8 Hz, Ar—H) · (M +− 50) 7.29(1 H, s, Ar—H) · 7.39(1 H, d, J = 8 Hz,Ar—H) · 9.25(1 H, s, OH) 9.47(1 H, s, OH)

[0343] TABLE 5 Example melting point NMR No (centi degree) NMR solventIR Appearance Mass UV 35 167.4-168.2 1.02(3 H, t, J = 7 Hz, CH3) · CDCI33340- 332 λ max nm (ε) · 2.01(1 H, sev, J = 7 Hz, CH2) · 2973- (M+,base) 244.4 (22900) · 280.4 2.48(3 H, s, SCH3) · 2912- (25700) · 34882.49(1 H, sev, J = 7 Hz, CH2) · 2879- (7100) 4.83(1 H, t, J = 7 Hz, CH)· 1618- 6.24(1 H, s, Ar—H) · 1594- 6.63(1 H, s, Ar—H) · 1489- 7.04(1 H,dd, J = 8.2 Hz, 1466- Ar—H) 7.17(1 H, s, Ar—H) · 7.53(1 H, d, J = 8 Hz,Ar—H) · ?(1 H, ?, OH) · 13.40(1 H, s, OH) 36 199.6-200.5 0.96(3 H, t, J= 7 Hz, CH3) · DMSO-d6 3487- brown 332(M+, base) λ max nm (ε) · 2.00(1H, sev, J = 7 Hz, CH2) · 3271- powder 207.2 (28200) · 248.8 2.44(1 H,sev, J = 7 Hz, CH2) · 2974- (21100) ·264.0 2.55(3 H, s, SCH3) · 2935-(23800) · 280.8 4.67(1 H, t, J = 7 Hz, CH) · 2914- (21200) · 339.67.00(1 H, s, Ar—H) · 2877- (4700) 7.16(1 H, d, J = 8 Hz Ar—H) 1644-7.19(1 H, s, Ar—H) · 1606- 7.55(1 H, s, Ar—H) · 1586- 7.67(1 H, d, J = 8Hz, Ar—H) · 1499- 9.92(2 H, brs, OH) 1456 37 1.54(3 H, d, J = 6.7 Hz,CH3) · DMSO-d6 3490- λ max nm (ε) · 4.84(1 H, q, J = 6.7 Hz, CH) · 3274-204.4 (22800) · 243.6 6.96(1 H, s, Ar—H) · 1645- (15900) · 257.2 7.24(1H, t, J = 7.4 Hz, Ar—H) · 1601- (15000) · 3384 7.39(1 H, d, J = 7.7 Hz,Ar— 1581- (3700) H) · 7.46(1 H, t, J = 7.4 Hz, Ar—H) · 1509 7.51(1 H, s,Ar—H) · 7.68(1 H, d, J = 7.5 Hz, Ar—H) · 38 175.0-177.5 0.98(3 H, t, J =7 Hz, CH3) · DMSO-d6 3332- 286 ε max 8811 (λ 2.05(1 H, sev, J = 7 Hz,CH2) · 2977- (M+, base)- max 340.0 nm) · ε 2.44(1 H, sev, J = 7 Hz, CH2)· 2887- 271 (M +− max 13046 (λ max 4.84(1 H, t, J = 7 Hz, CH) · 1621-15) - 253 299.6 nm) · ε max 6.23(1 H, d, J = 2 Hz, Ar—H) · 1591- (M +−33)- 25492 (λ max 6.70(1 H, d, J = 2 Hz, Ar— 241.8 nm) · ε max H) ·7.35(1 H, t, J = 8 Hz, Ar—H) · 30052 (λ max 7.46(1 H, d, J = 8 Hz Ar—202.4 nm) H) · 7.57(1 H, t, J = 8 Hz, Ar—H) · 7.77(1 H, d, J = 8 Hz, Ar—H) · 10.97(1 H, brs, OH) 13.30(1H 39 152.1-153.4 1.62(3 H, d, J = 7 Hz,CH3) · DMSO-d6 3271- ε max 8221 (λ 5.09(1 H, q, J = 7 Hz, CH) · 1618-max 340.0 nm) · ε 6.23(1 H, d, J = 2 Hz, Ar—H) · 1594- max 12798 (λ max6.70(1 H, d, J = 2 Hz, Ar— 299.2 nm) · ε max H) · 7.35(1 H, t, J = 8 HzAr—H) · 24627 (λ max 7.49(1 H, d, J = 8 Hz Ar— 241.2 nm) · ε max H) ·7.57(1 H, t, J = 8 Hz, Ar—H) · 44124 (λ max 7.76(1 H, d, J = 8 Hz, Ar—202.4 nm) · H) · 10.96(1 H, brs, OH) 13.41(1 H, s, OH) · 40 67.5-68.33.41-3.47(1 H, m, CH2) · DMSO-d6 3338- yellow 348 λ max nm (ε)·3.73-3.74(1 H, m, CH) · 1620- powder (M+, base)- 241.2 (19600) · 300.85.38-5.40(3 H, m, CH3) · 1583 330 (M +− (10600) · 340.0 6.23(1 H, d, J =2 Hz, Ar—H) · 18)-257 (6500) 6.70(1 H, d, J = 2 Hz, Ar—H) · (M +−91)-229 7.18(1 H, t, J = 8 Hz, Ar—H) · (M +− 119) 7.26-7.42(5 H, m,Ar—H) · 7.55(1 H, t, J = 8 Hz, Ar—H) · 7.66(1 H, d, J = 8 Hz Ar—H) ·7.75(1 H, d, J = 8 Hz Ar— H) · 11.00(1 H, brs, OH) 13.22(1 H, s, OH) ·41 190.0-191.6 1.68(3 H, d, J = 6.7 Hz, CH3) · CDCI3 3324- colorless256(M+, ε max 20467 (λ max 4.94(1 H, dd, J = 13.2,6.7 Hz, CH2) · 1656-needle Base) 256.0 nm)·· 5.55(1 H, s, OH) · 1589 crystal 6.76(1 H, dd, J= 8.8.2,2.2 Hz, CH) · 7.05(1 H, d, J = 2.1 Hz Ar—H) · 7.17(1 H, td, J =6.8,2.3 Hz, Ar—H) · (2 H, q, Ar—H) 7.64(1 H, d, J = 7.7 Hz, Ar—H) ·8.13(1 H, d, J = 8.7 Hz, Ar—H) 42 1.01 (3 H, t, J = 7.2 Hz, CH3) · CDCI33398- 286-253-229 ε max 20284 (λ max 2.02-2.09(1 H, m, CH2) · 2969- 244nm) · ε max 2.50-2.58(1 H, m, CH2) · 2877- 34443 ( λ max 4.91(1 H, dd, J= 8.2,6.0 Hz, CH) · 1652- 204.4 nm) 6.1 (2 H, s, OH) · 6.9 1595- (1 H,dd, J = 8.6 Hz, Ar—H) · 1471- 7.04 (1 H .d Ar—H) · 7.16(1 H, m, Ar—H) ·7.36 (1 H, m, Ar—H) · 7.40 (1 H, mAr—H) · 7.64 (1 H,mAr—H) · 7.83 (1 H,d, J = 8.6 Hz, Ar—H) 43 0.77(6 H, t, J = 7 Hz, CH3) · DMSO-d6 3365- 360λ max nm (ε) · 1.98(2 H, six, J = 7 Hz, CH2) 2968- (M+, base)- 254.0(9717) · 284.0 2.25(2 H, six, J = 7 Hz, CH2) · 2923- 345 (M +− (11907) ·362.0 2.54(3 H, s, SCH3) · 2879- 15)-275 (2323) · 6.31 (1 H, d, J = 2 HzAr—H) 1617- (M +− 85) 6.34(1 H, d, J = 2 Hz, Ar—H) 1576- 7.15(1 H, dd, J= 8.2 Hz, Ar—H) · 1457- 7.32(1 H, d, J = 2 Hz, Ar— H) · 7.55(1 H, d, J =8 Hz, Ar—H) 9.96(2 H, brs, OH) · 10.03(2 H, br 44 235.6-237.4 0.87(3 H,t, J = 7.3 Hz, CH3) · 3517- needle 366(M+, λ max nm (ε) · 1.89(1 H, sev,J = 6.8 Hz, CH2) · 3294- crystal pale Base)- 246.4 (30500) · 258 2.35(1H, sev, J = 7.3 Hz, CH2) · 2974- violet 364-333- (sh 27400) · 280 (sh4.59(1 H, t, J = 7.1 Hz, CH) · 2960- 331-309- 16200) · 340.0 6.94(1 H,s, Ar—H) · 2936- 307-285 (6800) · 7.41(1 H, dd,J = 8,2 Hz, Ar—H) 1647-7.44(1 H, s, Ar—H) · 1597- 7.46(1 H, s, Ar—H) · 1586- 7.62(1 H, d, J = 8Hz, Ar—H) · 1507- (2 H, brs, OH) 1461

[0344] TABLE 6 Example melting point NMR No (centi degree) NMR solventIR Appearance Mass UV 45 227.2- 0.95(3 H, t, J = 7.2 Hz, CH3) · DMSO-d63516- pinkish- 366 (M+, λ max nm (ε) · 229.9 1.96-2.01(1 H, m, CH2) ·3307- white Base)-364 337.6 (5600) · 280.8 2.38-2.44(1 H, m, CH2) ·2968- needle (12000) · 257.2 4.64(1 H, t, J = 7.2 Hz, CH) · 2877-crystal (25600) · 241.6 7.02(1 H, s, Ar—H) · 1645- (28100) · 205.27.35(1 H, d, J = 8.4 Hz, Ar—H) · 1596- (36100) 7.56(1 H, s, Ar—H) ·1506- 7.71(1 H, dd, J = 1.7, 8.4 Hz, Ar—H) · 1463 7.97(1 H, d, J = 1.7Hz, Ar—H) · 10.04(2 H, brs, OH) · 46 179.8- 0.98(3 H, t, J = 7 Hz, CH3)· DMSO-d6 3514- λ max nm (ε) 183.0 2.04(2 H, m, J = 7 Hz, CH2) · 3289-2.25(2 H, m, J = 7 Hz, CH2) · 2970- 2.44(1 H, sev, J = 7 Hz, CH2) ·2936- 2.47(3 H, s, SCH3) · 2877- 4.71(1 H, t, J = 7 Hz, CH) · 1645-6.40(2 H, brs, OH) · 1598- 7.00(1 H, m, Ar—H) · 1505 7.10(1 H, m, J = 8Hz, Ar—H) 7.16(1 H, m, Ar—H) · 7.22(1 H, m, Ar—H) · 7.54(1 H, s, Ar—H) ·7.90(2 H, brs, OH) · 8.01(1 H, 47 121.0- 0.850(3 H, t, J = 7.5 Hz, −CH3)· DMSO-d6 3328- colorless ε max 7180 (λ max 123.0 1.540(2 H, Sx, J = 7.5Hz, 2959- needle 325.2 nm) · −CH3) · 2.509(2 H, t, 7.5 Hz, −CH2) · 2929-crystal ε max 6924 (λ max 4.044(2 H, s, CH2) · 2869- 313.6 nm) · 6.063(1H, d, J = 2.2 Hz, Ar—H) · 1636- ε max 15843 (λ 6.337(1 H, d, J = 2.2 Hz,Ar—H) · 1592- max 287.2 nm) · ε 7.094(1 H, dd, J = 8.1, 1.4 Hz, Ar—H) ·1498- max 4214 (λ max 7.204(1 H, d, J = 8.1 Hz, Ar—H) · 1445 253.2 nm) ·7.214(1 H, s, Ar—H) · ε max 40043 (λ 10.969(1 H, s, Ph—OH) max 204.0 nm)48 179.1- 1.22(3 H, t, J = 8 Hz, CH3) · CDCI3 3315- colorless 286 (M+, λmax nm (ε) · 180.1 2.64(2 H, q, J = 8 Hz, CH2) · 2964- needle base)241.2 (21400) · 262.8 4.35(2 H, brs, CH2) · 2931- crystal (14700) ·301.6 5.76(1 H, brs, OH) · 2872- (11200) · 340.0 6.25(1 H, d, J = 2 Hz,Res-H) · 1618- (7800) 6.67(1 H, d, J = 2 Hz, Res-H) · 1594 7.06(1 H, dd,J = 8,1 Hz, Ar—H) · 7.27(1 H, d, J = 1 Hz Ar—H) · 7.52(1 H, d, J =8,Ar—H) · 13.53(1 H, s, OH) 49 1.15(3 H, t, J = 7.1 Hz, CH3) · DMSO-d63339- amorphous 270-241 λ max nm (ε) · 2.58(2 H, q, J = 7.1 Hz, CH2) ·2968- 287.2 (12600) · 327.2 4.03(2 H, s, CH2) · 2932- (6700) 6.07(1 H,d, J = 2.5 Hz, Ar—H) · 1637- 6.36(1 H, d, J = 2.5 Hz, Ar—H) · 1597-7.05-7.25(3 H, m, Ar—H) · 1506- 11.00(1 H, brs, OH) · 1446 13.00(1 H, s,OH) 50 105.6- 0.94(3 H, t, J = 7 Hz, CH3) · DMSO-d6 3314- white 298 λmax nm (ε) · 106.8 1.33(2 H, Sx, J = 7 Hz, CH2) · 2956- needle (M+,base)- 204.4 (36300) · 220.0 1.58(2 H, quintet, J = 7 Hz, CH2) · 2929-crystal 269 (M +− (sh.28100) · 287.2 2.61 (2 H, t, J = 7 Hz, CH2) ·2860- 29)-255 (15000) · 326.0 4.11(2 H, s, CH2) · 1636- (M +− 43)-241(6900) 6.13(1 H, d, J = 2 Hz, Ar—H) · 1498- (M +− 57) 6.40(1 H, d, J = 2Hz, Ar—H) · 1445- 7.16(1 H, d, J = 8 Hz, Ar—H) · 7.28(2 H, dd, J = 8.2Hz, Ar— H) · 11.05(1 H,brs, Ph—OH) · 13.07(1 H, s, Ph—OH) 51 125.9-2.9(4 H, m, CH2) · 4.02(2 H, s, CH2) · CDCI3 3482- colorless 346(M+)- εmax 7420 (λ max 127.7 6.16(1 H, d, J = 2.5 Hz, Ar—H) · 2923- amorphous255(base) 325.2 nm) 6.36(1 H, d, J = 2.5 Hz, Ar— 2859- ε max 7063 (λ maxH) · 7.0-7.3(8 H, m, Ar—H) · 1636- 312.8 nm) 13.04(1 H, s, OH) 1507- εmax 1 4590( λ max 1447 286.8 nm) ε max 6445( λ max 257.2 nm) ε max54184(λ max 204.0 nm) 52 0.91(3 H, t, J = 6 Hz, CH3) · CDCI3 3310- oil298(M+, ε max 7414 (λ max 1.2-1.7(4 H, m, CH2 × 2) · 2959- base)-241324.0 nm) · 2.59(2 H, t, J = 7 Hz, CH2) · 2933- ε max 7140 (λ max 4.02(2H, s, CH2) · 2860- 313.6 nm) · 6.0(1 H, brs, Ph—OH) · 1636- ε max 15675(λ 6.16(1 H, d, J = 2 Hz, Ar—H) · 1595- max 286.8 nm) · ε max 6.38(1 H,d, J = 2 Hz Ar—H) · 1508- 4885(λ max 6.9-7.3(3H , m, Ar—H) · 1445 254.8nm) · 13.04(1 H, s, Ph—OH) ε max 40878 (λ max 204.8 nm) 53 106.9- 0.94(3H,t, J = 7 Hz, CH3) · DMSO-d6 3308- pale 314 (M+, λ max nm (ε) · 108.11.34(2 H, qt, J = 7.7 Hz, CH2) · 2929- yellow base) 204.0 (46000) ·241.6 1.58(2 H, tt, J = 7.7 Hz, CH2) · 2859- needle (22500) · 263.62.64(2 H, t, J = 7 Hz, CH2) · 1618- crystal (15600) · 301.6 4.37(2 H, s,CH2) · 6.24(1 H, d, J = (11 800) · 340.0 2 Hz, Ar—H) · (8000) 6.70(1 H,d, J = 2 Hz, Ar—H) · 6.19(1 H, d, J = 8.2 Hz, Ar— H) · 7.41(1 H, d, J =2 Hz, Ar—H) · 7.62(1 H, d, J = 8 Hz, Ar— H) · 11.02(1 H, brs, OH) ·13.52(1 H, s, OH) 54 170.3- 4.25(2 H, s, CH2) · 6.17(1 H, d, J = DMSO-d63465- colorless 318 (M+, λ max nm (ε) · 172.0 2 Hz, Ar—H) · 3032- needlebase) 204.8 (55366) · 255.6 6.47(1 H, d, J = 2 Hz, Ar—H) · 1644- crystal(25351) · 284.0 7.42(1 H, tt, J = 8.1 Hz, Ar— 1592 (sh.16957) · 320.0 H)· 7.48(1 H, d, J = 8 Hz, Ar—H) · (6840) 7.52(2 H, t, J = 8 Hz, Ar— H) ·7.66(1 H, dd, J = 8.2 Hz, Ar—H) · 7.72(2 H, dd, J = 8.1 Hz, Ar—H) ·7.81(1 H, d, J = 2 Hz, Ar—H) · 11.10(1 H, brs, OH) · 13.10(1 H, s, OH)

[0345] TABLE 7 Example melting point NMR No (centi degree) NMR solventIR Appearance Mass UV 55 293.9-300.1 4.25(2 H, s, CH2) · 6.16(1 H, d, J= DMSO-d6 3427- yellow 319 (M+, λ max nm (ε) · 2 Hz, Ar—H) · 1637 powderbase) 203.6 (20952) · 256.0 6.46(1 H, d, J = 2 Hz, Ar—H) · (10308) ·279.2 7.50-7.55(2 H, m, Ar—H) · (10274) · 317.5 (3383) 7.73(1 H, d, J =8 Hz, Ar—H) · 7.89(1 H, s, Ar—H) · 8.12(1 H, d, J = 8 Hz, Ar—H) · 8.62(1H, s, Ar—H) · 8.94(1 H, s, Ar—H) · 11.15(1 H, brs, OH) · 13.08(1 H, s,OH) 56 244.3-250.7 4.28(2 H, s, CH2) · 6.16(1 H, d, J = DMSO-d6 3502-colorless 363 (M+, λ max nm (ε) · 2 Hz, Ar—H) · 3085- amorphous base)204.8 (49743) · 255.6 6.47(1 H, d, J = 2 Hz, Ar—H) · 1641- (32260)·327.6 (9997) 7.53(1 H, d, J = 8 Hz, Ar— 1593 H) · 7.79-7.83(2 H, m,Ar—H) · 7.99(1 H, d, J = 2 Hz, Ar—H) · 8.21(1 H, d, J = 8 Hz, Ar—H) ·8.27(1 H, dd, J = 8.2 Hz, Ar—H) · 8.52(1 H, t, J = 2 Hz, Ar—H) · 11.12(1H, brs, OH) · 13.09(1 H, s, OH) 57 171.0-172.7 4.15(2 H, s, CH2) ·6.09(1 H, d, J = DMSO-d6 3543- pinkish 308 (M+, λ max nm (ε) · 2 Hz,Ar—H) · 3468- white base)-279 203.5 (30330) · 220.0 6.38(1 H, d, J = 2Hz, Ar—H) · 3062- needle (M +− 29) (sh.24545) · 282.0 6.59(1 H, dd, J =3.2 Hz, Ar—H) · 1641 crystal (30829) · 320.5 (6430) 6.95(1 H, d, J = 3Hz, Ar—H) · 7.38(1 H, d, J = 8 Hz, Ar—H) · 7.63(1 H, dd, J = 8.2 Hz, Ar—H) · 7.75(1 H, s, Ar—H) · 7.78(1 H, d, J = 2 Hz, Ar—H) · 11 ?(1 H, brs,OH) · 13.00(1 H, s, OH) 58 199.9-201.0 4.17(2 H, s, CH2) · 6.10(1 H, d,J = DMSO-d6 3369- pale yellow 324(M+, base) λ max nm (ε) · 2 Hz, Ar—H) ·3111- needle 203.6 (3996) · 225.0 6.38(1 H, d, J = 2 Hz, Ar—H) · 1645-crystal (sh.26343) · 284.4 7.13(1 H, dd, J = 4.5 Hz, Ar— 1601- (33237) ·3300 H) · 7.37(1 H, d, J = 8 Hz, Ar—H) · (sh,7905) 7.51(1 H, dd, J = 4.1Hz, Ar—H) · 7.55(1 H, dd, J = 5.1 Hz, Ar—H) · 7.59(1 H, dd, J = 8.2 Hz,Ar—H) · 7.76(1 H, d, J = 2 Hz, Ar—H) · 11.?(1 H, brs, OH) · 13.01(1 H,s, OH). 59 >300 4.23(2 H, s, CH2) · 5.21(2 H, brs, NH2) · DMSO-d6 3368-pale yellow 333(M+, base) λ max nm (ε) · (decom- 6.15(1 H, d, J = 2 Hz,Ar—H) · 3280- plate 206.4 (35877) · 229.5 position) 6.45(1 H, d, J = 2Hz, Ar—H) · 1641- crystal (sh.27582) · 285.0 6.62(1 H, dd, J = 8.2 Hz,Ar—H) · 1606 (12124) · 319.0 6.82(1 H, d, J = 8 Hz, Ar—H) · (sh.6503)6.88(1 H, d, J = 2 Hz, Ar— H) · 7.14(1 H, t, J = 8 Hz, Ar—H) · 7.44(1 H,d, J = 8 Hz, Ar—H) · 7.52(1 H, dd, J = 8.2 Hz, Ar—H) · 7.67(1 H, d, J =2 Hz, Ar—H) · ?(1 H, brs, OH) · 13.09( 60 174.0-175.0 2.34(2 H, s, CH3)· 4.17(2 H, s, CH2) · DMSO-d6 3503- pale yellow 332(M+, base) λ max nm(ε) · 6.09(1 H, d, J = 2 Hz, Ar—H) · 3031- powder 206.0 (53935) · 260.46.39(1 H, d, J = 2 Hz, Ar—H) · 2917- (27534) · 320.8 (7109) 7.26(2 H, d,J = 8 Hz, Ar—H) · 1640- 7.39(1 H, d, J = 8 Hz, Ar—H) · 1591 7.54-7.58(3H, m, Ar—H) · 7.72(1 H, d, J = 2 Hz, Ar—H) · ?(1 H, brs, OH) · 13.04(1H, s, OH) 61 208.9-213.6 4.19(2 H, s, CH2) · 6.10(1 H, d, J = DMSO-d63503- pale brown 352 λ max nm (ε) · 2 Hz, Ar—H) · 2919- powder (M+,base) 212.0 (52265) · 258.8 640(1 H, d, J = 2 Hz, Ar—H) · 1645- (24168)· 280.0 7.40-7.43(2 H, m, Ar—H) · 1593 (sh.17980) · 319.0 7.48(1 H, t, J= 8 Hz, Ar—H) · (6840) 7.63-7.66(2 H, m, Ar—H) · 7.74(1 H, t, J = 2 Hz,Ar—H) · 7.82(1 H, d, J = 2 Hz, Ar— H) · ?(1 H, brs, OH) · 1303(1 H, s,OH) 62  91.8-94.8 2.21(2 H, s, CH3) · 4.16(2 H, s, CH2) · DMSO-d6 3556-yellow 332 λ max nm (ε) · 6.11(1 H, d, J = 2 Hz, Ar—H) · 3467- powder(M+, base) 207.6 (50567) · 2868 6.41(1 H, d, J = 2 Hz, Ar—H) · 3060-(14377) · 3220 (6601) 7.18(1 H, dd, J = 7,2 Hz, Ar—H) · 1637-7.17-7.21(4 H, m, Ar—H) · 1602 7.39(1 H, d, J = 8 Hz, Ar—H) · 741(1 H,d, J = 2 Hz, Ar—H) · ?(1 H, brs, OH) · 1304(1 H, s, OH) 63 151.5-155.01.20(3 H, t, J = 7.1 Hz, CH3) · DMSO-d6 3314- 346-332- λ max nm (ε) ·2.2(4 H, m, CH2) · 1629 285-275 286.8 (14800) · 4.03(2 H, s, CH2) ·6.16(1 H, d, J = 2.5 Hz, Ar—H) · 6.38(1 H, d, J = 2.5 Hz, Ar—H) · 6.55(1H, brs, OH) · 7.0- 7.7(8 H, m, Ar—H) · 13.02(1 H, s, OH) 64 191 7-195.04.21(2 H, s, CH2) · 6.10(1 H, d, J = DMSO-d6 3502- white 386 λ max nm(ε) · 2 Hz, Ar—H) · 3057- needle (M+, base) 208.0 (50083) · 257.6 6.41(1H, d, J = 2 Hz, Ar—H) · 1647- crystal (23573) · 280.0 7.45(1 H, d, J = 8Hz, Ar— 1594 (sh.18210) · 321.0 H) · 7.68-7.74(3 H, m, Ar—H) · (6975)7.89(1 H, dt, J = 8. 2 Hz, Ar—H) · 7.98-8.00(2 H, m, Ar—H) · ?(1 H, brs,OH) · 13.04(1 H, s, OH) 65 274.0- 2.67(2 H, s, CH3) · 4.27(2 H, s, CH2)· DMSO-d6 3195- pinkish- 360(M+, base) λ max nm (ε) · 279.0 6.16(1 H, d,J = 2 Hz, Ar—H) · 1677- white 204.8 (44022) · 285.6 (decom- 6.47(1 H, d,J = 2 Hz, Ar—H) · 1641- powder (32630) position) 7.52(1 H, d, J = 8 Hz,Ar—H) · 1606 7.76(1 H, dd, J = 8.2 Hz, Ar—H) · 7.88-7.92(3 H, m, Ar—H) ·8.09(2 H, d, J = 8 Hz, Ar—H) · ?(1 H, brs, OH) · 13.09(1 H, s, OH) 66173.8-175.8 1.60-1.61(4 H, m, CH2 * 2) · DMSO-d6 3322- mud brown364(M+)- ε max 16815 (λ max 2.16(2 H, m, CH2) · 2940- amorphous109(Base)- 286.4 nm) · 2.30(2 H, m, CH2) · 1640- 81 ε max 10407 (λ4.05(2 H, s, CH2) · 1606 max 4.11(2 H, s, CH2) · 262.4 nm) 6.13(1 H, d,J = 2 Hz, Ar—H) · 6.41(1 H, d, J = 2 Hz, Ar—H) · 7.16(1 H, d, J = 8.2Hz, Ar— H) · 7.23(1 H, t, J = 4 Hz, CH) · 7.26(1 H, d, J = 2 Hz, Ar— H)· 7.29(1 H, d, J = 8 Hz, Ar—H) · 11.0(1 H, br, OH) · 13.05(1 H, s, OH)

[0346] TABLE 8 Example melting point NMR Appear- No (centi degree) NMRsolvent IR ance Mass UV 67 228.4-230.8 2.44(2 H, s, Ar—CH3) · DMSO-d63210- white λ max nm 2.64(2 H, s, CH3) · 2977- powder (ε) · 207.6 4.20(2H, s, CH2) · 2926- (46800) · 6.10(1 H, d, J = 1637- 238,0 2 Hz, Ar—H) ·1591- (sh.37400) · 6.41(1 H, d, J = 1508- 261.0 2 Hz, Ar—H) · 1446(sh.6300) · 7.37(1 H, dd, J = 284.0 8.2 Hz, Ar—H) · (sh.19000) · 7.43(1H, d, J = 3224 8 Hz, Ar—H) · (9400) 7.68(1 H, dt, J = 8.2 Hz, Ar—H) ·7.73(1 H, dt, J = 8.2 Hz, Ar—H) · 7.85(1 H, d, J = 2 Hz, Ar—H) · 8.05(1H, d, J = 2 Hz, Ar—H) · 11.05(1 H, brs, OH) · 13 68 195.5-195.81.57-1.61(4 H, m, CH2 * 2) · DMSO-d6 3244- pale 364 ε max 15975 2.16(2H, m, CH2) · 2938- yellow (M+)- (λ max 2.31(2 H, m, CH2) · 2874- amor-255- 287.2 nm) · 4.09(2 H, s, CH2) · 1629- phous 109- ε max 4.12(2 H, s,CH2) · 1507- 81 7762 (λ max 6.14(1 H, d, J = 1447 261.6 nm) · 2 Hz,Ar—H) · ε max 6.41(1 H, d, J = 46059 (λ 2 Hz, Ar—H) · max 206.0 nm)7.11(1 H, d, J = 8. 2 Hz, Ar—H) · 7.21(1 H, m, CH) · 7.26(1 H, m, Ar—H)· 7.39(1 H, d, J = 8 Hz, Ar—H) · 11.0(1 H, br, OH) · 13.07(1 H, s, OH)69 199.9-201.4 4.22(2 H, s, CH2) · DMSO-d6 3354- color- 352(M+, ε max6.16(1 H, d, J = 1634- less Base)- 7572 (λ 2.3 Hz, Ar—H) · 1605 needlemax 322.4 6.50(1 H, d, J = crystal nm) · ε 2.3 Hz, Ar—H) · max 160687.48-7.83(7 H, m, Ar—H) · (λ max 11.11(1 H, brs, OH) · 284.4 nm) ·13.08(1 H, s, OH) ε max 21047 (λ max 257.2 nm) 70 249.6-250.8 4.18(2 H,s, CH2) · DMSO-d6 3250- yellow 308(M+)- ε max 6.16(1 H, d, J = 1633-needle 279 (Base) 10430.2 (λ 2.1 Hz, Ar—H) ·  884 crystal max 320.26.49(1 H, d, J = nm) · ε 2.1 Hz, Ar—H) · max 30636.9 6.67(1 H, q, J = (λ max 1.6 Hz, Furyl-H) · 279.6 nm) · 71(1 H, d, J = 3.4 Hz, Furyl-H) ·7.53(1 H, d, J = 7.9 Hz, Ar—H) · 7.63(1 H, d, J = 7.9 Hz, Ar—H) · 7.72(1H, s, Ar—H) · 7.82(1 H, s, Ar—H) · 11.11(1 H, brs, OH) · 13.06(1 H, s,OH). 71 208.8-210.2 2.4(3 H, s, CH3) · DMSO-d6 3328- yellow 332(M+, εmax 4.2(2 H, s, CH2) · 1636- needle Base) 7458 (λ 6.16(1 H, d, J = 2.3Hz, Ar—H) · 1595 crystal max 320.6 6.49(1 H, d,J = 2.3 Hz, Ar—H) · nm) ·ε 7.33(2 H, d, J = 8.0 Hz, Ar—H) · max 23077 7.53-7.69(5 H, m, Ar—H) ·(λ max 11.10(1 H, brs, OH) · 262.2 nm) · 1309(1 H, s, OH) 72 163.5-165.82.28(3 H, s, CH3) · DMSO-d6 3377- pinkish- 332(M+, ε max 4.22(2 H, s,CH2) · 1633- white Base) 6656 (λ 6.16(1 H, d, J = 1.3 Hz, Ar—H) · 1591amor- max 322.0 6.46(1 H, d, J = 1.2 Hz, Ar—H) · phous nm) · ε7.24-7.56(7 H, m, Ar—H) · max 14655 11.09(1 H, brs, OH) · (λ max 13.1(1H, s, OH) 287.0 nm) · 73 183.0-184.7 4.23(2 H, s, CH2) · DMSO-d6 3290-pale 386(M+, ε max 6.17(1 H, d, J = 1633- yellow Base) 7394 (λ 2.2 Hz,Ar—H) · 1594- needle max 323.2 6.51(1 H, d, J = 2.1 Hz, Ar—H) · 1336crystal nm) · ε 7.60-7.85(5 H, m, Ar—H) · max 16194 8.08(2 H, d, J = 1.9Hz, Ar—H) · (λ max 11.11(1 H, brs, OH) · 286.0 nm) · 13.07(1 H, s, OH) εmax 21318 (λ max 256.2 nm) 74 228.3-230.0 4.19(2 H, s, CH2) · DMSO-d63393- yellow 333(M+, ε max 5.22(2 H, brs, NH2) · 3309- amor- Base) 9332(λ 6.16(1 H, d, J = 2.2 Hz, Ar—H) · 1637- phous max 322.0 6.49(1 H, d, J= 2.4 Hz, Ar—H) · 1572 nm) · ε 6.62-6.65(1 H, m, Ar—H) · max 149376.87(2 H, t, J = 13.8 Hz, Ar—H) · (λ max 7.15(1 H, t, J = 7.8 Hz, Ar—H)· 287.4 nm) · 7.46-7.56(3 H, m, Ar— ε max H) · 11.09(1 H, brs, OH) ·34865 13.09(1 H, s, OH) · (λ max 223.4 nm) 75 241.0-247.08 4.25(2 H, s,CH2) · DMSO-d6 crude crude 6.15(1 H, d, J = (CNS-183- (CNS-183- 2 Hz,Ar—H) · 20%

) 20%

6 46(1 H, d, J = 2 Hz, Ar—H) · 7.39-7.51(3 H, m, Ar— H) · 7.55- 7.70(2H, m, Ar—H) · 7.74(1 H, dt, J = 8. 2 Hz, Ar—H) · 7.94(1 H, s, Ar—H) ·8.38(1 H, s, OH) · 10.32(1 H, s, OH) · 11.?(1 H, brs, OH) · 13.09(1 H,s, OH) 76 240.1-246.1 4.46(2 H, s, CH2) · DMSO-d6 3331- 340 λ max 6.25(1H, d, J = 3091- (M+, nm (ε) · 2 Hz Ar—H) · 1598 base)- 244.4 6.72(1 H,d, J = 2 Hz, Ar—H) · 307 (M +− (22300) · 7.22(1 H, dd, J = 33)-279 297.25.4 Hz, Ar—H) · (M +− 61) (30000) · 7.62-7.68(3 H, m, Ar—H) · 343.07.74(1 H, d, J = 8 Hz, Ar—H) · (sh.1000) 7.95(1 H, s, Ar—H) · 11.08(1 H,brs, OH) · 13.52(1 H, s, OH) 77 212.6-215.7 4.49(2 H, s, CH2) · DMSO-d63619- 350 λ max 6.26(1 H, d, J = 3478- (M+, nm (ε) · 2 Hz, Ar—H) · 3393-base) 268.0 6.74(1 H, d, J = 2 Hz Ar—H) · 3184- (19100) · 7.46(1 H, t, J= 7 Hz Ar—H) · 1640- 287.6 7.54(2 H, t, J = 7 Hz, Ar—H) · 1601 (20900) ·7.66(1 H, dd, J = 322.0 8.2 Hz, Ar—H) · (7400) 7.76(2 H, d, J = 7 Hz,Ar—H) · 7.81(1 H, d, J = 8 Hz, Ar—H) · 7.91(1 H, d, J = 2 Hz, Ar—H) ·11.06(1 H, brs, OH) · 13.55(1 H, s, OH)

[0347] TABLE 9 Example melting point NMR Appear- No (centi degree) NMRsolvent IR ance Mass UV 78 190.8-195.3 4.49(2 H, s, CH2) · 6.26(1 H, d,J = DMSO-d6 3332- 334 λ max nm (ε)· 2 Hz, Ar—H) · 3073- (M+, 246.4(26400) · 282.4 6.74(1 H, d, J = 2 Hz, Ar—H) · 1598 base)- (20800) ·344.0 (6900) 7.46(1 H, t, J = 7 Hz, Ar—H) · 301 (M +− 7.54(2 H, t, J = 7Hz, Ar—H) · 33) 7.66(1 H,dd, J = 8.2 Hz, Ar—H) · 7.76(2 H, d, J = 7 Hz,Ar—H) · 7.81(1 H, d, J = 8 Hz, Ar—H) · 7.91(1 H, d, J = 2 Hz, Ar—H) ·11.07(1 H, brs, OH) · 13.55(1 H, s, OH) 79 >250 4.27(2 H, s, CH2) ·6.16(1 H, d, J = DMSO-d6 3370- 394 ε max 52384.9 (λ max (decom- 2 Hz,Ar—H) · 1638 (M+, 283.0 nm) · ε max position) 6.47(1 H, d, J = 2 Hz,Ar—H) · base) 88456.4 (λ max 7.43-7.56(4 H, m, Ar—H) · 208.4 nm) 7.73(1H, dd, J = 8.2 Hz, Ar—H) · 7.79-7.83(6 H, m, Ar—H) · 7.88(1 H, d, J = 2Hz, Ar—H) · 11.08(1 H, brs, OH) · 13.01(1 H, s, OH) 80 >250 4.51(2 H, s,CH2) · 6.26(1 H, d, J = DMSO-d6 3421- 379 λ max nm (ε) · (decom- 2 Hz,Ar—H) · 3090- (M+, 247.6 (45100) · 282.7 position) 6.74(1 H, d, J = 2Hz, Ar—H) · 2911- base)- (27100) · 340.0 (10900) 7.77-7.88(3 H, m, Ar—H)· 2360- 346 (M +− 8.67(1 H, s, Ar—H) · 1617 33) 8.24(1 H, d, J = 8 Hz,Ar—H) · 8.30(1 H, dd, J = 8.2 Hz, Ar—H) · 8.55(1 H, d, J = 2 Hz, Ar—H) ·11.06(1 H, brs, OH) · 13.55(1 H, s, OH) · 81 214.3-215.3 4.37(2 H, s,CH2) · 6.21(1 H, d, J = DMSO-d6 3310- pale ε max 7707 (λ max 2.4 Hz,Ar—H) · 1616- yellow 340.0 nm) · ε max 6.69(1 H, d, J = 2.3 Hz, Ar—H) ·1591- amor- 19923 (λ max 7.14(1 H, dd, J = 5.2, 3.7 Hz,  701 phous 286.4nm) · ε max Ar—H) · 7.54- 14694 (λ max 7.6(3 H, m, Ar—H) · 7.71(1 H, dd,241.6 nm) · ε max J = 7.9, 1.9 Hz, Ar— 17445 (λ max H) · 7.95(1 H, d, J= 1.9 Hz, 204.8 nm) Ar—H) · 13.46(1 H, s, OH) 82 234.9-238.8 4.36(2 H,s, CH2) · 6.20(1 H, d, J = DMSO-d6 3226- pinkish- 324(M+, ε max 9678 ( λmax 2.4 Hz, Ar—H) · 1611- white Base) 340.0 nm) · ε max 6.60(1 H, dd, J= 3.4, 1.9 Hz, 1575- amor- 29245 (λ max Ar—H) · 885 phous 282.0 nm) · εmax 6.68(1 H, d, J = 24 Hz, Ar—H) · 17358 (λ max 7.06(1 H, d, J = 3.2 HzAr—H) · 239.2 nm) · ε max 7.55(1 H, d, J = 6 Hz, Ar—H) · 17404 (λ max7.75(2 H, dd, J = 7.7, 1.7 Hz, 204.8 nm) Ar—H) · 7.99(1 H, d, J = 1.6Hz, Ar—H) · 13.46(1 H, s, OH) · 83 >200 4.47(2 H, s, CH2) DMSO-d6 3364-349 λ max nm (ε)- (decom- 5.25(2 H, s, NH2) · 3295- (M+, 204.8 (30900) ·243.6 position) 6.25(1 H, d, J = 2 Hz, Ar—H) · 1582 base) (26500) ·281.6 6.65(1 H, d, J = 8 Hz, Ar—H) (161 00) · 337.0 (6400) 6.73(1 H, d,J = 2 Hz, Ar—H) · 6.86(1 H, d, J = 8 Hz, Ar—H) · 6.92(1 H, s, Ar—H) ·7.17(1 H, t, J = 8 Hz, Ar—H) · 7.54(1 H, d, J = 8 Hz, Ar—H) · 7.77(2 H,m, Ar—H) · 11.02( 84 243.5- 4.45(2 H, s, CH2) · 6.26(1 H, d, J = DMSO-d63338- 324 λ max nm (ε)· 248.4 2 Hz, Ar—H) · 3075- (M+, 238.0 (sh.49100)· (decom- 6,68(1 H, dd, J = 3.2 Hz, Ar—H) · 1598 base)- 298.4 (26600) ·339.0 position) 6.72(1 H, d, J = 2 Hz, Ar—H) · 295 (21100) 7.15(1 H, d,J = 3 Hz, Ar— (M +− H) · 7.67(1 H, dd, J = 8,2 Hz, 29)-291 Ar—H) ·7.76(1 H, d, J = (M +− 8 Hz, Ar—H) · 7.85(1 H, s, Ar—H) · 33)-263 7.92(1H, s, Ar—H) · 11.05(1 H, s, OH) · (M +− 61) 13.51(1 H, s, OH) 85798.3-203.2 4.25(2 H, s, CH2) · 6.15(1 H, d, J = DMSO-d6 3467- 402 λ maxnm (ε) · 2 Hz, Ar—H) · 3069- (M+, 251.7 (19600) · 281.5 6.46(1 H, d, J =2 Hz, Ar—H) · 1650- base) (sh.45900) · 323.0 7.49-7.52(3 H, m, Ar— 1594(68000) H) · 7.69(1 H, dd, J = 8.2 Hz, Ar—H) · 7.84-7 86(3 H, m, Ar—H) ·11.06(1 H, m, OH) · 13.09(1 H, s, OH) 86 228.4-235.2 2.34(3 H, s, CH3) ·4.38(2 H, s, CH2) · DMSO-d6 3318- pale 348 ε max 10566 (λ max 6.21(1 H,d, J = 2.3 Hz, Ar—H) · 1619- yellow (M+, 342.2 nm) · ε max 6.69(1 H, d,J = 2.4 Hz, Ar—H) · 1589 amor- Base) 36653 (λ max 7.27(2 H, d, J = 8 Hz,Ar—H) · phous 259.4 nm) · ε max 7.58(3 H, t, J = 7.6 Hz, Ar—H) · 70816(λ max 7.71(1 H, dd, J = 7.9, 1.8 Hz, 203.8 nm) · Ar—H) · 7.92(1 H, d, J= 1.8 Hz, Ar—H) · 13.48(1 H, s, OH) · 87 209.7-212.0 4.36(2 H, s, CH2)·6.21(1 H, s, CH2) · DMSO-d6 3295- pale 334 ε max 8621 (λ max 6.7(1 H,s, Ar—H) · 1618- yellow (M+, 340.0 nm) · ε max 7.39-7.95(7 H, m, Ar—H) ·1590 needle Base) 13242 (λ max 7.94(1 H, s, Ar—H) · crystal 300.8 nm) ·ε max 13.48(1 H, s, OH) · 35927 ( λ max 245.2 nm) · ε max 64276 (λ max2056 nm) 88 124.0-125.8 4.19(2 H, s, CH2) · 6.46(1 H, s, DMSO-d6 3401-yellow 334 ε max 16414 (λ max Ar—H) · 7.36- 1640- needle (M+, 295.6 nm)· ε max 7.74(8 H, m, Ar—H) · 1600 crystal Base) 34018 (λ max 12.98(1 H,s, OH) · 248.8 nm) · ε max 71778 (λ max 204.4 nm)

[0348] TABLE 10 Example melting point NMR No (centi degree) NMR solventIR Appearance Mass UV 89 178.1-198.3 2.21(3 H, s, CH3) · DMSO-d6 3340-pale yellow 348 ε max 11569 (λ 4.40(2 H, s, CH2) · 1591 amorphous (M+,Base) max 340.0 nm) · ε 6.21(1 H, s, J = needle max 12408 (λ max 2.3 Hz,Ar—H) · crystal 300.0 nm) · ε max 6.67(1 H, s, J = 36540 (λ max 2.3 Hz,Ar—H) · 241.2 nm) · ε max 7.20-7.62(7 H, m, Ar—H) · 70476 (λ max 13.48(1H, s, OH) · 203.2 nm) 90 180.3-191.6 4.46(2 H, s, CH2) · DMSO-d6 3329-brown 368 ε max 6061 (λ 6.26(1 H, d, J = 2.1 Hz Ar—H) · 1617- needle(M+, Base) max 340.0 nm) · ε 6.74(1 H, d, J = 2.2 Hz, Ar—H) · 1594-crystal max 9184 (λ max 7.49-8.06(7 H, m, Ar—H) ·  782 amorphous 298.4nm) · ε max 11.07(1 H, brs, OH) · 23829 (λ max 13.52(1 H, s, OH) 240.0nm) · ε max 46353 (λ max 210.0 nm) 91 225.3-226.5 4.48(2 H, s, CH2) ·6.26(1 H, d, J = DMSO-d6 3314- pale brown 402 λ max nm (ε) · 2.3 Hz,CH2) · 1615- needle (M+, Base) 254.4 (32300) · 301.6 6.75(1 H, d, J =2.4 Hz, Ar—H) · 1588- crystal (12700) · 340.0 7.7-7.90(4 H, m, Ar— 1335(8300) H) · 8.06-8.13(3 H, q, Ar—H) · 11.08(1 H, brs, OH) · 13.52(1 H,s, OH) 92 251.6-253.8 4.48(2 H, s, CH2) · 6.27(1 H, d, J = DMSO-d6 3209-orange 374 ε max 27125 (λ max 2.2 Hz, Ar—H) · 3180- needle (M+, Base)302.0 nm) · ε max 6.77(1 H, d, J = 2.3 Hz, Ar—H) · 1610- crystal 31051(λ max 7 33- 1575 236.4 nm) · 7.74(7 H, m, Ar—H) · 8.03-8.06(1 H, q,Ar—H) · 8.28(1 H, d, J = 1.3 Hz, Ar—H) · 11.13(1 H, brs, OH) · 13.52(1H, s, OH) 93 >250 4.21(2 H, s, CH2) · 6.15(1 H, d, J = DMSO-d6 3459- 350ε max 25618 (λ max 2 Hz, Ar—H) · 3291- (M+, base) 277.6 nm) · ε max6.44(1 H, d, J = 2 Hz, Ar—H) · 3170- 56647 (λ max 6.86(1 H, d, J = 8 Hz,Ar— 1647 206.0 nm) · H) · 6.98(1 H, dd, J = 8.2 Hz, Ar—H) · 7.07(1 H, d,J = 2 Hz, Ar—H) · 7.39(1 H, d, J = 8 Hz, Ar—H) · 7.50(1 H, dd, J = 8.2Hz, Ar—H) · 8.08(1 H, s, Ar—H) · 9.05(1 H, brs, OH) · 9.13(1 H, brs, OH)· 11.07(1 H, brs, OH) · 13.09(1 H, s, OH) · 94 268.4-268.5 4.27(2 H, s,CH2) · 6.17(1 H, d, J = DMSO-d6 3340- ε max 29487 (λ 2 Hz, Ar—H) · 1641max 322.0 nm) · ε 6.47(1 H, d, J = 2 Hz, Ar—H) · max 41425 (λ max 7.33(1H, t, J = 8 Hz, Ar—H) · 307.2 nm) · ε max 7.39(1 H, t, J = 8 Hz, Ar—H) ·41043 (λ max 7.50(1 H, s, Ar—H) · 291.2 nm) · ε max 7.53(1 H, d, J = 8Hz, Ar—H) · 56920 (λ max 7.68(1 H, d, J = 8 Hz, Ar—H) · 205.6 nm) 7.73(1H, d, J = 8 Hz, Ar—H) · 7.93(1 H, dd, J = 8.2 Hz, Ar—H) · 8.08(1 H, s,Ar—H) · 11.13(1 H, brs, OH) · 13.07(1 H, s, O 95 257.9-259.9 4.16(2 H,s, CH2) · 6.10(1 H, d, J = DMSO-d6 3339.2- yellow 358 (M+, ε max 22612(λ max 2.3 Hz, Ar—H) · 1633.9- needle Base)-329 323 nm) · ε max 6.46(1H, d, J = 2.4 Hz, Ar—H) · 1609.8- crystal 30616 (λ max 307.6 7.28(1 H,t, J = 7.4 Hz, Ar—H) ·  881.6 nm) · ε max 31103 7.33(1 H, m, Ar—H) · (λmax 290.0 nm) · 7.53(1 H, s, Ar—H) · ε max 52850 (λ 7.57(1 H, d, J =7.9Hz, Ar—H) · max 204.8 nm) 7.65(2 H, q, Ar—H) · 7.81 (1 H, dd, J = 7.8,1.5 Hz, Ar—H) · 7.89(1 H, d, J = 1.3 Hz, Ar—H) · 11.10(1 H, br, OH) ·13.00(1 H, s, OH) 96 261.6-263.2 4.16(2 H, s, CH2) · 6.1(1 H, d, J =DMSO-d6 3347- pale yellow 394 (M+, ε max 45218 (λ max 2.2 Hz Ar—H) ·1633- amorphous Base) 281.2 nm) · ε max 6.45(1 H, d, J = 2.4 Hz, Ar—H) ·1614 83321 (λ max 206.4 7.4(1 H, d, J = 7.3 Hz, Ar—H) · nm) 7.47-7.54(1H, m, Ar—H) · 7.62(1 H, d, J = 1.7 Hz, Ar—H) · 7.72-7.82(7 H, m, Ar—H) ·10.97(1 H, br, OH) · 13.03(1 H, s, OH) 97 197.7-200.8 4.16(2 H, s, CH2)· 6.08(1 H, d, J = DMSO-d6 3258- pale yellow 402 (M+, ε max 11227 (λ max20 Hz, Ar—H) · 6.41(1 H, d, J = 1629- needle Base) 322.8 nm) · ε max 2.2Hz, Ar—H) · 1586- crystal 20844 (λ max 7.44(2 H, d, J = 8.3 Hz, Ar—H) ·1263 280.4 nm) · ε max 7.52-7.59(2 H, m, Ar—H) · 29734 (λ max 252.47.69(1 H, s, Ar—H) · nm) · ε max 75178 7.82(2 H, d, J = 8.6 Hz, Ar—H) ·(λ max 203.6 nm) 11.05(1 H, br, OH) · 13.02(1 H, s, OH) 98 229.8-231.64.10(2 H, s, CH2) · 6.08(1 H, d, J = DMSO-d6 3288- pale brown 350 (M+, εmax 24641 (λ max 2.3 Hz, Ar—H) · 1641- amorphous Base) 286.4 nm) · ε max6.41(1 H, d, J = 2.3 Hz, Ar—H) · 1598 63587 (λ max 6.8(1 H, d, = 8.2 Hz,Ar—H) · 204.4 nm) · 6.96(1 H, dd, J = 6.2,2.2 Hz, Ar—H) · 7.04(1 H, d, J= 2.2 Hz, Ar—H) · 7.39(1 H, dd, J = 7.9,1.5 Hz, Ar—H) · 7.43(1 H, d, J =7.9 Hz, Ar—H) 7.48(1 H, d, J = 1.2 Hz, Ar—H) · 9.01(1 H, br, OH) ·9.13(1 H, br, OH) · 11.03(1 H, 99 pale yellow 340 (M+)- λ max nm (ε) ·amorphous 324-295 207.2(22300) · 227.0 (Base) (22100) · 239.0 (16300) ·287.6 (15500) · 331.2 (6400)

[0349] TABLE 11 Example melting point NMR No (centi degree) NMR solventIR Appearance Mass UV 100 239.1-242.6 4.09(2 H, s, CH2) · 6.08(1 H, d, J= DMSO-d6 3467- pale brown 350 (M+, ε max 21818 (λ max 2.3 Hz, Ar—H) ·3256- needle Base) 287.6 nm) · ε max 6.3(1 H, dd, J = 8.3, 2.3 Hz, 1638-crystal 20338 (λ max Ar—H) · 6.37(1 H, d, J = 1593 265.6 nm) · ε max 2.2Hz, Ar—H) · 63304 (λ max 202.4 6.40(1 H, d, J = 2.3 Hz, Ar—H) · nm)7.07(1 H, d, J = 8.4 Hz, Ar—H) · 7.34(1 H, dd, J = 7.8, 1.3 Hz, Ar—H) ·7.37(1 H, d, J = 7.9 Hz, Ar—H) · 7.44(1 H, d, J = 0.9 Hz, Ar—H) · 9.38(1H, br, OH) · 9.47(1 H, s, OH) · 11(1 H, br, O 101 189.4-191.1 4.23(2 H,s, CH2) · 6.17(1 H, d, J = DMSO-d6 3348- pale yellow 342(M+, ε max 40436(λ max 2.4 Hz, Ar—H) · 1633- amorphous Base) 283.6 nm) · 6.48(1 H, d, J= 2.4 Hz, Ar—H) · 1609- ε max 18280 (λ max 7.4-7.6(8 H, m, Ar— 1505249.2 nm) · H) · 11.2(1 H, brs, OH) · 13.04(1 H, s, OH) ε max 56341 (λmax 204.4 nm) 102 135.6-137.6 0.833(3 H, t, J = 6 Hz, CH3) · DMSO-d63434- colorless ε max 3707(λ max 1.15-1.35(6 H, m, CH2) · 3364-amorphous 275.2 nm) · 1.504(2 H, t, J = 6 Hz, CH2) · 2956- ε max 3404 (λmax 2.482(2 H, t, J = 8 Hz, CH2) · 2924- 262.8 nm) · 2.728(2 H, t, J = 6Hz, CH2) · 2855- ε max 52641 (λ max 2.955(2 H, t, J = 6 Hz, CH2) · 1624-206.4 nm) 6.026(1 H, d, J = 2 Hz, Ar—H) · 1498- 6.072(1 H, d, J = 2 Hz,Ar—H) · 1457 6.91-6.97(2 H, m, Ar— H) · 6.700(1 H, s, Ar—H) · 9.127(1 H,s, Ph—OH) · 9.302(1 H, s, Ph—OH) 103 153.3-154.8 1.66(2 H, quintet, J =3 Hz, CH2) · 3423- colorless λ max nm (ε) · 2.49-2.54(2 H, m, CH2) ·3318- amorphous 206.0 (52200) · 275.2 0.73(2 H, t, J = 5 Hz, CH2) ·2939- (3800) 0.73(2 H, t, J = 5 Hz, CH2) · 1618- 2.49-2.54(2 H, m, CH2)· 1497- 4.41(1 H, t, J = 4 Hz, R—OH) · 1461 6.02(1 H, s, Ar—H) · 6.07(1H, s, Ar—H) · 6.95(2 H, s, Ar—H) · 7.01 (1 H, s, Ar—H) · 9.12(1 H, s,Ph—OH) · 9.31(1 H, s, Ph—OH) 104 0.73(3 H, t, J = 7 Hz, CH3) · DMSO-d63338- 284 λ max nm (ε) · 1.13(3 H, d, J = 7 Hz, CH3) · 2961- (M+, base)-206.0 (53000) · 274.4 1.50(2 H, quintet, J = 7 Hz, 2928- 269 (M +−(3900) CH2) · 2.49(1 H, m, CH) · 2873- 15)-255 2.73(2 H, t, J = 6 Hz,CH2) · 1624- (M +− 29) 2.97(2 H, t, J = 6 Hz, CH2) · 1496- 6.03(1 H, d,J = 2 Hz, Ar—H) · 1458 6.07(1 H, d, J = 2 Hz, Ar—H) · 6.96(2 H, m, Ar—H)· 7.01(1 H, m, Ar—H) · 9.13(1 H, s, Ph—OH) · 9.31(1 H, s, Ph—OH) 105125.2-126.9 −0.03(9 H, s, TMS) · DMSO-d6 3360- pale orange λ max nm (ε)· 0.78(2 H, t, J = 8 Hz, CH2) · 2954- needle 205.6 (57600) · 271.22.49-2.53(2 H, m, CH2) · 2923- crystal (4200) 2.72(2 H, m, CH2) · 2854-2.94(2 H, m, CH2) · 6.01(1 H, 1623- d, J = 2 Hz, Ar—H) · 1496- 6.06(1 H,d, J = 2 Hz, Ar—H) · 1457 6.95(2 H, m, Ar—H) · 7.03(1 H, m, Ar—H) ·9.14(1 H, s, Ph—OH) · 9.32(1 H, s, Ph—OH) ·· 106 2.86-2.89(2 H, m, CH2)· DMSO-d6 3402- yellow 349 (Base, λ max nm (ε) · 3.12-3.15(2 H, m, CH2)· 2926- oil M+), 204.4 (60000) 6.18(1 H, d, J = 2858- 252.8 (28700) 2.4Hz, Ar—H) · 1623- 6.21(1 H, d, J = 1508- 2.4 Hz, Ar—H) · 7.41- 14587.43(1 H, m, Ar—H) · 7.55-7.60(2 H, m, Ar—H) · 7.80(1 H, t, J = 8 Hz,Ar—H) · 8.20-8.27(2 H, m, Ar—H) · 8.48-8.49(2 H, m, Ar—H) · 9.25(1 H,br, OH) · 9.44(1 H, br, OH) · 107 2.56-2.57(2 H, m, CH2) · DMSO-d6 3378-pale yellow oil 319 (Base, λ max nm (ε) · 3.08-3.11(2 H, m, CH2) · 2921-M+) 206.0 (57700) 5.19(2 H, brs, NH2) · 2851- 6.17(1 H, d, J = 2.4 Hz,Ar—H) · 1623- 6.18(1 H, d, J = 2.4 Hz, Ar—H) · 1509- 6.61(1 H, dd, J =8.2 Hz, Ar—H) · 1457 6.82(1 H, d, J = 8 Hz, Ar—H) · 6.89(1 H, m, J = 2Hz, Ar— H) · 7.14(1 H, t, J = 8 Hz, Ar—H) · 7.32(2 H, m, Ar—H) · 7.42(1H, m, Ar—H) · 9.25(1 H, br, OH) · 9.43(1 H, br, 108 169.1-174.92.79-2.82(2 H, m, CH2) · DMSO-d6 3469- 332 (M+)- ε max 2548 (λ max2.89(4 H, s, CH2 * 2) · 3368- 241 (Base) 340.6 nm) · 3.01-3.04(2 H, m,CH2) · 1621 6.11(1 H, d, J = 2.1 Hz, Ar— H) · 6.15(1 H, d, J = 2.1 Hz,Ar—H) · 6.97-7.35(8 H, m, Ar—H) · 9.21(1 H, br, OH) · 9.39(1 H, br, OH)· 109 176.7-179.2 2.85-2.89(2 H, m, CH2) · DMSO-d6 3437- 304 ε max21325.6 (λ max 3.13-3.16(2 H, m, CH2) · 3361- (M+, base) 258.0 nm) · εmax 6.15(1 H, d, J = 2 Hz, Ar—H) · 68335.7 (λ max 6.17(1 H, d, J = 2 Hz,Ar— 204.6 nm) H) · 7.21(1 H, d, J = 8 Hz, Ar—H) · 7.39(1 H, t, J = 8 Hz,Ar—H) · 7.48- 7.52(3 H, m, Ar—H) · 7.58(1 H, d, J = 2 Hz, Ar—H) · 7.68(2H, d, J = 8 Hz, Ar—H) · 9.25(1 H, s, OH) · 9.44(1 H, s, OH) · 110194.2-195.6 2.79(2 H, t, J = 6.3 Hz, CH2) · DMSO-d6 3440- pale gray310(M+, ε max 12818 ( λ max 3.02(2 H, t, J = 6.3 Hz, Ar—H) · 3368-needle Base) 282.8 nm) · ε max 6.13(2 H, t, J = 2.8 Hz, Ar—H) · 2923-crystal 35269 (λ max 7.07-7.14(1 H, m, Ar—H) · 2856- 205.2 nm) · 7.26(1H, d, J = 7.8 Hz, Ar—H) · 1623- 7.35-7.38(2 H, m, Ar—H) ·  6987.51-7.54(2 H, m, Ar—H) · 9.21(1 H, s, OH) · 9.4(1 H, s, OH)

[0350] TABLE 12 Example melting point NMR No (centi degree) NMR solventIR Appearance Mass UV 111 188.3-191.4 2.83-2.87(2 H, m, CH2) · DMSO-d63369- 310 ε max 22325(λ 3.10-3.13(2 H, m, CH2) · 687- (M+, base) max284.4 nm) · ε max 6.14(1 H, d, J = 2 Hz, 64475(λ max Ar—H) · 6.17(1 H,d, 204.4 nm) J = 2 Hz, Ar— H) · 7.16-7.19(2 H, m, Ar—H) · 7.48- 7.51(2H, m, Ar—H) · 7.55-7.58(2 H, m, Ar—H) · 9.25(1 H, s, OH) · 9.45(1 H, s,OH)· 112 195.1-197.1 2.33(3 H, s, CH3) · DMSO-d6 3432- pale pink 318(M+,Base) ε max 21032(λ max 2.8(2 H, t, J = 3362- needle 256.4 nm) · ε max6.3 Hz, CH2) · 1625- crystal 56257(λ max 3.09(2 H, t, J = 1612 207.6nm)· 6.3 Hz, CH2) · 6.12(2 H, dd, J = 6.1, 2.4 Hz, Ar—H) · 7.24-7.36(5H, m, Ar—H) · 7.54(2H, d, J = 8.1 Hz, Ar—H) · 9.23(1 H, s, OH) · 9.41(1H, s, OH) 113 151.8-152.7 2.78-2.84(2 H, m, DMSO-d6 3440- 332 (M+)- εmax 4037.3(λ CH2) · 2.88- 3368 241(M⁺⁻ max 275.4 nm) · ε max 2.91(4 H,m, CH2) · 91, base) 69082.7(λ max 3.01-3.04(2 H, m, 206.2 nm) CH2) ·6.10(1 H, d, J = 2 Hz, Ar— H) · 6.14(1 H, d, J = 2 Hz, Ar—H) ·7.01-7.07(2 H, m, Ar—H) · 7.12(1 H, d, J = 2 Hz, Ar—H) · 7.21-7.25(1 H,d, J = 2 Hz, Ar—H) · 7.27-7.28(2 H, d, J = 2 Hz, Ar—H) · 7.31-7.35(2 H,d, J = 2 Hz, Ar—H) · 9.20(1 H, s, OH) · 9.39(1 H, s, OH) 114 163.6-173.92.83-2.86(2H, m, DMSO-d6 3432- 294 ε max 24574.5(λ max CH2) · 3.10-3.153370 (M+, base) 283.0 nm) · ε max (2 H, m, CH2) · 52361.3(λ max 6.13(1H, d, J = 204.8 nm) 2 Hz, Ar—H) · 6.16(1 H, d, J = 2 Hz, Ar—H) · 6.63(1H, m, Ar—H) · 6.91(1 H, d, J = 3 Hz, Ar—H) · 7.19(1 H, d, J = 8 Hz,Ar—H) · 7.55(1 H, dd, J = 8.2 Hz, Ar—H) · 7.63(1 H, d, J = 2 Hz, Ar—H) ·7.77(1 H, s, Ar—H) · 9.25(1 H, s, OH) · 9.45(1 H, s, OH) 115 198.6-201.12.79(2 H, m, CH2) · DMSO-d6 3456- colorless 294(M+, Base) ε max 25034(λmax 3.02(2 H, t, J = 3362- needle 282.2 nm) · ε max 6.3 Hz, CH2) · 2924-crystal 39332(λ max 6.12(2 H, s, Ar—H) · 2856- 207.8 nm) · 6.58(1 H, dd,J = 1622- 3.3, 1.8 Hz, Ar—H) · 874 6.94(1 H, d, J = 3.4 Hz, Ar—H) ·7.26(1 H, t, J = 4.1 Hz, Ar—H) · 7.39-7.41(2 H, m, Ar—H) · 7.72(1 H, d,J = 1.6 Hz, Ar—H) · 9.25(1 H, brs, OH) · 9.43(1H, brs, OH) 116 2.23(3 H,s, CH3) · DMSO-d6 3410- pale pink 318(M+, Base) ε max 23012(λ max 2.82(2H, t, J = 3348- oil 228.2 nm) · ε max 6.3 Hz, Ar—H) · 2923- 22380(λ max3.06(2 H, t, J = 2847- 221.8 nm)· 6.3 Hz, Ar—H) · 1622- 6.10(2 H, dd, J= 751 11.2, 2.3 Hz, Ar—H) · 7.02- 7.29(8 H, m, Ar—H) · 9.22(1 H, s, OH)· 9.43(1 H, s, OH) 117 150.2-152.6 2.81(2 H, t, J = DMSO-d6 3370- palepink 372(M+, Base) ε max 18307(λ max 6.3 Hz, CH2) · 2923- amorphous253.2 nm) · ε max 3.07(2 H, t, J = 2853- 56560(λ max 6.3 Hz, CH2) ·1624- 206.6 nm)· 6.12(1 H, d, J = 1336- 2.4 Hz, Ar—H) · 1174- 6.15(1 H,d, J = 1129 2.4 Hz, Ar—H) · 7.35(1 H, d, J = 7.82 Hz, Ar—H) ·7.45-7.50(2 H, td, Ar—H) · 7.67- 7.73(2 H, m, Ar—H) · 7.96-7.99(2 H, m,Ar—H) · 9.24(1 H, brs, OH) · 9.43(1 H, brs, OH) 118 137.1-143.2 2.81(2H, t, J = DMSO-d6 3445- colorless 338(M+, Base) ε max 20038(λ max 6.3Hz, CH2) · 3370- amorphous 253.2 nm) · ε max 3.05(2 H, t, J = 2922-61114(λ max 6.3 Hz, CH2) · 2855- 207.6 nm)· 6.12(1 H, d, J = 1622- 2.4Hz, Ar—H) · 785 6.15(1 H, d, J = 2.4 Hz, Ar—H) · 7.31(1 H, d, J = 7.8Hz, Ar—H) · 7.4-7.49(4 H, m, Ar—H) · 7.63(1 H, dd, J = 6.4, 1.3 Hz,Ar—H) · 7.72(1 H, t, J = 1.8 Hz, Ar—H) · 9.24(1 H, s, OH) · 9.43(1 H, s,OH) · 119 197.2-199.3 2.85-2.88(2 H, m, DMSO-d6 3371- 319 λ max nm(ε)·CH2) · 3.11-3.14 3224- (M+, base) 307.0(sh, 12300) (2H, m, CH2) · 3059-5.17(2H, br, N— 2885- H2) · 6.14(1 H, 2622- d, J = 2 Hz, 1618- Ar—H) ·6.17(1 H, d, J = 2 Hz, Ar—H) · 6.59(1 H, d, J = 8 Hz, Ar— H) · 6.79(1 H,d, J = 8 Hz, Ar—H) · 6.86(1 H, s, Ar—H) · 7.13(1 H, t, J = 8 Hz, Ar—H) ·7.18(1 H, d, J = 8 Hz, Ar—H) · 7.49(1 H, dd, J = 8.2 Hz, Ar—H) · 7.45(1H, s, Ar— H) · 9.25(1 H, b 120 199.6-201.8 2.87-2.90(2 H, DMSO-d6 3401-349 λ max nm(ε) · m, CH2) · 3.16- 2920- (M+, base)- 260.8(26800) · 323.53.19(2 H, m, CH2) · 1626 322(M⁺− (3500) 6.16(1 H, d, J = 17)- 2 Hz,Ar—H) · 6.18(1 H, d, J = 2 Hz, Ar—H) · 7.28(1 H, d, J = 8 Hz, Ar—H) ·7.64(1 H, dd, J = 8.2 Hz, Ar—H) · 7.72-7.74(1 H, m, Ar—H) · 7.78- 7.82(1H, m, Ar—H) · 8.18(1 H, d, J = 8 Hz, Ar—H) · 8.25(1 H, dd, J = 8.2 Hz,Ar—H) · 8.47(1 H, s, Ar—H) · 9.27(1 H, s, OH) · 9.47( 121 2.88(2 H, t, J= DMSO-d6 3369- λ max nm(ε) · 6 Hz, CH2) · 1624- 204.0(57600) · 261.63.16(2 H, t, J = 1476 (16600) 6 Hz, CH2) · 6.16(1 H, s, Ar—H) · 6.18(1H, d, J = 2 Hz, Ar—H) · 7.26(1 H, d, J = 8 Hz, Ar—H) · 7.51(1 H, dd, J =8.4 Hz, Ar—H) · 7.55(1 H, d, J = 8 Hz, Ar—H) · 7.65(1 H, s, Ar—H) ·8.09(1 H, d, J = 8 Hz, Ar—H) · 8.60(1 H, d, J = 4 Hz, Ar—H) · 8.91(1 H,s, Ar—H) · 9.26(1 H, s, OH) · 9.46(1 H, s, OH) ·

[0351] TABLE 13 Example melting point NMR No (centi degree) NMR solventIR Appearance Mass UV 122 211.8-217.3 2.84-2.87(2 H, DMSO-d6 3373- 253 λmax nm(ε) · m, CH2) · 3.09- 2237- (M+, base)- 226.5(sh, 52500) · 3.12(2H, m, CH2) · 1608 236 (M⁺⁻ 281.0(sh, 13900) · 6.15(1 H, d, J = 17) 2 Hz,Ar—H) · 6.19(1 H, d, J = 2 Hz, Ar—H) · 7.34(1 H, d, J = 8 Hz, Ar—H) ·7.72(1 H, dd, J = 8.2 Hz, Ar—H) · 7.80(1 H, s, Ar—H) · 9.33(1 H, s, OH)· 9.55(1 H, s, OH) · 123 196.1-198.5 2.99(2 H, q, J = DMSO-d6 3429- palebrown 326(M+, Base) ε max 27602(λ max 3.8 Hz, CH2) · 3370- amorphous279.6 nm) · ε max 3.23(2 H, q, J = 1609- 54275(λ max 3.9 Hz, CH2) · 692207.6 nm) 6.26(1 H, d, J = 2.4 Hz, Ar—H) · 6.34(1 H, d, J = 2.4 Hz,Ar—H) · 7.12(1H, dd, J = 5.0, 3.6 Hz, Ar—H) · 7.3(1 H, d, J = 8 Hz,Ar—H) · 7.51-7.54(3 H, m, Ar—H) · 7.67(1 H, d, J = 1.9 Hz, Ar—H) ·9.29(1 H, s, OH) · 9.52(1 H, s, OH) 124 148.5-149.6 3.04(2 H, q, J =DMSO-d6 3428- pale orange 310(M+, Base) ε max 22619(λ max 4.1 Hz, CH2) ·3366- amorphous 275.6 nm) · ε max 3.29(2 H, q, J = 1605- 57427(λ max 3.9Hz, CH2) · 829 205.6 nm) 6.31(1 H, d, J = 2.3 Hz, Ar—H) · 6.39(1 H, d, J= 2.4 Hz, Ar—H) · 6.64(1 H, dd, J = 3.6, 1.7 Hz, Ar—H) · 7.03(1 H, d, J= 3.1 Hz, Ar—H) · 7.36(3 H, d, J = 8.0 Hz, Ar—H) · 7.62(1 H, dd, J =7.6, 1.8 Hz, Ar—H) · 7.79(2 H, d, J = 1.7 Hz, Ar—H) · 9.3(1 H, s, OH) ·9.53(1 H, s, OH) 125 175.1-178.3 2.92(2 H, q, J = DMSO-d6 3494- palebrown 320(M+, Base) ε max 24764(λ 3.7 Hz, CH2) · 3462- amorphous max254.4 nm) · ε 3.15(2 H, t, J = 3421- max 64910(λ max 6.2 Hz, CH2) · 1627204.4 nm) 6.26(1 H, s, Ar—H) · 7.19-7.68(8 H, m, Ar—H) · 8.08(1 H, brs,OH) · 8.37(1 H, brs, OH) · 9.06(1 H, brs, OH) 126 207.3-208.13.03-3.06(2 H, DMSO-d6 3435- ε max 21933(λ m, CH2) · 3.33-3.36 3369- max308.0 nm) ·ε (2 H, m, CH2) · 1607 max 61186(λ max 6.30(1 H, d, J = 202.4nm) 2 Hz, Ar—H) · 6.36(1 H, d, J = 2 Hz, Ar— H) · 7.19(1 H, dd, J = 5.3Hz, Ar—H) · 7.47(1 H, d, J = 8 Hz, Ar—H) · 7.50(1 H, d, J = 8 Hz, Ar— H)· 7.57(1 H, d, J = 3 Hz, Ar—H) · 7.61(1 H, d, J = 5 Hz, Ar—H) · 7.62(1H, s, Ar—H) · 9.28(1 H, s, OH) · 9.52(1 H, s, OH) 127 213.7-214.73.02-3.05(2 H, m, DMSO-d6 3447- ε max 26495(λ CH2) · 3.32-3.35 3376- max301.2 nm) · ε (2 H, m, CH2) · 1607- max 55066(λ max 6.30(1 H, d, J =207.6 nm) 2 Hz, Ar—H) · 6.36(1 H, d, J = 2 Hz, Ar— H) · 6.65(1 H, dd, J= 3.2 Hz, Ar—H) · 7.01(1 H, d, J = 3 Hz, Ar—H) · 7.49-7.54(1 H, m, Ar—H)· 7.67(1 H, s, Ar—H) · 7.80 (1 H, s, Ar—H) · 9.28(1 H, s, OH) · 9.52(1H, s, OH) 128 157.6-157.9 0.90(3 H, t, J = DMSO-d6 3353- colorless298(M+)- ε max 13003(λ max 7 Hz, CH3) · 3170- needle 255(Base) 261.2 nm)· ε 1.60(2 H, tq, J = 2964- crystal max 12385(λ 7.7 Hz, CH2) · 1652- max245.6 nm) · ε 2.94(2 H, t, J = 1622- max 53218(λ 7 Hz, CH2) · 2.79(2H,1597 max 206.8 nm) m, CH2) · 3.08(2 H, m, CH2) · 6.07(1 H, d, J = 2 Hz,Ar—H) · 6.11(1 H, d, J = 2 Hz, Ar—H) · 7.18(1 H, d, J = 8 Hz, Ar—H) ·7.78(1 H, dd, J = 2.8 Hz, Ar—H) · 7.83(1 H, d, J = 2 Hz, Ar—H) · 9.23 (1H, br, OH) · 9.43(1 H, br, OH) 129 151.8-152.8 0.90(3 H, t, J = DMSO-d63360- pale pink 314(M+)- ε max 9626(λ max 7 Hz, CH3) · 2959- amorphous271(Base) 315.6 nm) · ε 1.60(2 H, tq, J = 1679- max 5918(λ max 7.7 Hz,CH2) · 1591 276.4 nm) · ε 2.94(2 H, t, J = max 44639(λ 7 Hz, CH2) · 2.99max 208.4 nm) (2 H, m, CH2) · 3.25(2 H, m, CH2) · 6.25(1 H, d, J = 2 Hz,Ar—H) · 6.30(1 H, d, J = 2 Hz, Ar—H) · 7.50(1 H, d, J = 8 Hz, Ar—H) ·7.68(1 H, dd, J = 2.8 Hz, Ar—H) · 7.80(1 H, d, J = 2 Hz, Ar—H) · 9.30(1H, br, OH) · 9.48(1 H, br, OH) 130 119.8-121.7 0.88(3 H, t, J = DMSO-d63367- colorless 312(M+)- ε max 12405(λ max 7 Hz, CH3) · 3203- needle255(Base) 260.0 nm) · ε 1.32(2 H, tq, J = 2946- crystal max 12019(λ 7.7Hz, CH2) · 1656- max 245.6 nm) · ε 1.56(2 H, tt, J = 1597 max 51546(λ7.7 Hz, CH2) · max 206.4 nm) 2.79(2 H, m, CH2) · 2.95(2 H, t, J = 7 Hz,CH2) · 3.06 (2 H, m, CH2) · 6.07(1 H, d, J = 2 Hz, Ar—H) · 6.11(1 H, d,J = 2 Hz, Ar—H) · 7.18(1 H, d, J = 8 Hz, Ar—H) · 7.78(1 H, dd, J = 2.8Hz, Ar—H) · 7.83(1 H, d, J = 2 Hz, Ar—H) · 9.23(1 H, br, OH) · 9.43(1 H131 155.1-158.7 0.88(3 H, t, J = DMSO-d6 3429- pinkish 328(M+)- ε max10260(λ max 7 Hz, CH3) · 3370- white 271(Base) 314.8 nm) · ε 1.31(2 H,tq, J = 2957- amorphous max 6421(λ max 7.7 Hz, CH2) · 1678- 276.8 nm) ·ε 1.56(2 H, tt, J = 1591 max 48033(λ 7.7 Hz, CH2) · max 208.8 nm) 2.94(2H, t, J = 7 Hz, CH2) · 2.99(2 H, m, CH2) · 3.25(2 H, m, CH2) · 6.25(1 H,d, J = 2 Hz, Ar—H) · 6.30(1 H, d, J = 2 Hz, Ar—H) · 7.50(1 H ,d, J = 8Hz, Ar—H) · 7.68(1 H, dd, J = 2.8 Hz, Ar—H) · 7.80(1 H, d, J = 2 Hz,Ar—H) · 9.28(1 H, br, OH) · 9.49(1 H

[0352] TABLE 14 Example melting point NMR No (centi degree) NMR solventIR Appearance Mass UV 132 1.38-1.44(5 H, DMSO-d6 3348- oil 354(M+)- εmax 9403(λ max m, cyclo-hex) · 2930- 271(Base) 299.2 nm) · ε 1.77-1.83(5H, m, 2853- max 6935(λ max cyclo-hex) · 3.06(2 H, 1660- 277.6 nm) · ε m,CH2) · 3.32(2 H, 1589 max 47934(λ m, CH2) · 3.34(1 H, max 208.0 nm) m,cyclo-hex) · 6.32(1 H, d, J = 2.4 Hz, Ar—H) · 6.37(1 H, d, J = 2.4 Hz,Ar— H) · 7.58(1 H, d, J = 8.1 Hz, Ar—H) · 7.75 (1 H, dd, J = 1.6, 8.1Hz, Ar—H) · 7.85(1 H, d, J = 1.6 Hz, Ar—H) · 9.33(1 H, br, OH) · 9.57(1H, br, O 133 1.17(1 H, m, cyclo- DMSO-d6 3370- oil 338(M+)- ε max12018(λ max hex) · 1.25- 2931- 255(Base) 261.6 nm) · ε 1.46(4 H, m,cyclo- 2855- max 11355(λ hex) · 1.62- 1661- max 246.0 nm) · ε 1.78(5 H,m, cyolo- 1601 max 51180(λ hex) · 2.79(2 H, m, max 206.4 nm) CH2) ·3.06(2 H, m, CH2) · 3.34(1 H, m, cyclo-hex) · 6.07(1 H, d, J = 2 Hz,Ar—H) · 6.11(1 H, d, J = 2 Hz, Ar—H) · 7.18 (1 H, d, J = 8 Hz, Ar—H) ·7.78(1 H, dd, J = 2.8 Hz, Ar—H) · 7.82(1 H, d, J = 2 Hz, Ar— H) · 9.23(1H, br, OH) · 9.4 134 141.2-141.7 1.83(1 H, m, cyclo- DMSO-d6 3359-pinkish white 326(M+)- ε max 11180(λ max bu) · 2.07(1 H, m, 2944-amorphous 271(Base) 317.2 nm) · ε cyclo-bu) · 2.20- 1669- max 6902(λ max2.32(4 H, m, cyclo- 1591 277.2 nm) · ε bu) · 3.06(2H, m, max 51325(λCH2) · max 208.4 nm) 3.32(2 H, m, CH2) · 4.15(1 H, dddd, J = 8.5 Hz,each, cyclo-bu) · 6.32(1 H, d, J = 2.5 Hz, Ar—H) · 6.37(1 H, d, J = 2.5Hz, Ar—H) · 7.58(1 H, d, J = 8 Hz, Ar— H) · 7.68(1 H, dd, J = 2.8 Hz,Ar—H) · 7.79(1 H, d, J = 2 Hz, Ar—H) · 9.33(1 H 135 142.2-143.5 1.02(4H, m, cyclo- DMSO-d6 3371- pinkish white 312(M+, ε max 10456(λ max pro)· 2.85(1 H, 1660- amorphous Base)-271 317.6 nm) · ε m, cyclo-pro) · 1591max 6176(λ max 3.00(2 H, m, CH2) · 277.2 nm) · ε 3.27(2 H, m, CH2) · max47193(λ 6.26(1 H, d, J = max 208.8 nm) 3 Hz, Ar—H) · 6.31(1 H, d, J = 3Hz, Ar—H) · 7.53(1 H, d, J = 8 Hz, Ar—H) · 7.75(1 H, dd, J = 2.8 Hz,Ar—H) · 7.88(1 H, d, J = 2 Hz, Ar—H) · 9.26(1 H, brs, OH) · 9.51(1 H,brs, OH) 136 1.07(6 H, d, J = DMSO-d6 3332- oil 314(M+)- ε max 8618(λmax 6.8 Hz, CH3*2) · 2972- 271(Base) 316.0 nm) · ε 3.00(2 H, m, CH2) ·1664- max 5596(λ max 3.26(2 H, m, CH2) · 1589 276.8 nm) · ε 3.59(1 H, q,J = max 41069(λ 6.8 Hz, CH) · max 208.4 nm) 6.25(1 H, d, J = 2.4 Hz,Ar—H) · 6.30(1 H, d, J = 2.4 Hz, Ar— H) · 7.50(1 H, d, J = 8.1 Hz, Ar—H)· 7.69(1 H, dd, J = 1.6, 8.1 Hz, Ar—H) · 7.79(1 H, d, J = 1.6 Hz, Ar—H)· 9.26(1 H, br, OH) · 9.50(1 H, br, OH) 137 151.7-153.7 1.29(9 H, s,CH3*3) · CDCI3 3373- pinkish white 300(M+, ε max 10084(λ max 3.11(2 H,m, CH2) · 2963- amorphous Base)-285 274.4 nm) · ε 3.39(2 H, m, CH2) ·1604 max 7945(λ max 3.34(1 H, m, cyclo- 261.2 nm) · ε hex) · max 46454(λ4.8(1 H, br, OH) · max 204.0 nm) 4.9(1 H, br, OH) · 6.19(1 H, d, J = 2Hz, Ar—H) · 6.54(1 H, d, J = 2 Hz, Ar—H) · 7.15(1 H, dd, J = 2.8 Hz,Ar—H) · 7.22(1 H, d, J = 8 Hz, Ar— H) · 7.38(1 H, d, J = 2 Hz, Ar—H)·138 176.7-177.6 2.13(3 H, s, CH3) · DMSO-d6 3461- pale pink plate315(M+, Base)- ε max 16817(λ max 2.95(2 H, m, CH2) · 3370- crystal300-284 296.0 nm) · ε 3.23(2 H, m, CH2) · 1607 max 13182(λ 3.90(3 H, s,CH3) · max 6.23(1 H, d, J = 274.8 nm) · ε 2.4 Hz, Ar—H) · max 50814(λ6.28(1 H, d, J = max 210.4 nm) 2.4 Hz, Ar—H) · 7.40(2 H, m, Ar—H) ·7.52(1 H, m, Ar—H) · 9.20(1 H, br, OH) · 9.43(1 H, br, OH)· 139110.7-112.4 1.30-1.33(3 H, m, DMSO-d6 3452- colorless 329(M+, base)- εmax 14745.1(λ CH3) · 3.01-3.04 3371- amorphous 284 max 296.4 nm) · ε (2H, m, CH2) · 2938- max 14631.9(λ max 3.30-3.32(2 H, m, 1607 258.0 nm)CH2) · 4.20-4.26(2 H, m, CH2) · 6.32(1 H, d, J = 2.4 Hz, Ar—H) · 6.35(1H, d, J = 2.4 Hz, Ar—H) · 7.48(2 H, m, Ar—H) · 7.59(1 H, m, Ar—H) ·9.2(1 H, br, OH) · 9.5(1 H, br, OH) · 140 3.00-3.04(2 H, m, DMSO-d63276- colorless TMS

ε max 16018(λ max CH2) · 3.14-3.18, 2924- amorphous 447(M⁺ 1) 256.4 nm)· ε 3.45-3.47(2 H, m, 1674- max 14603(λ CH2) · 6.41(1 H, d, 1611- max J= 2.4 Hz, Ar—H) · 1057 244.8 nm) · ε 6.68(1 H, d, J = max 45362(λ 2.4Hz, Ar—H) · max 206.4 nm) 7.79(1H, d, J = 8.1 Hz, Ar— H) · 7.94(1 H, dd,J = 1.5 Hz, Ar—H) · 8.02(1 H, dd, J = 1.5, 8.1 Hz, Ar—H) · 9.63(1 H, s,OH) · 9.83(1 H, s, OH) 141 2.87-2.90(2 H, t, DMSO-d6 3366- white λ maxnm(ε) · J = 6 Hz, CH2) · 2924- 268.2(11100) · 253.2 3.13-3.16(2 H, t,1626- (12400) J = 6 Hz, CH2) · 1599- 6.17(1 H, d, J = 2 Hz, Ar—H) ·6.20(1 H, d, J = 2 Hz, Ar—H) · 7.31(1 H, d, J = 8 Hz, Ar—H) ·7.59-7.64(3H, m, Ar—H) · 7.71-7.74 (2H, m, Ar—H) · 7.78(2 H, d, J = 7Hz, Ar—H) · 9.31(1 H, s, OH) · 9.51(1 H, s, OH) 142 1.09(3 H, t, J =DMSO-d6 3369- 316 λ max nm(ε) · 7 Hz, CH3) · 2.52(3 H, 2966- (M+, base)-2052(31900)·218.8 s, SCH3) · 2.70- 2923- 301(M +− (32000) · 271.6 2.85(1H, m, CH2) · 2872- 15) · 283 (29000) 6.71(1 H, s, Ar—H) · 1595- (M +−33) · 269 6.85(1 H, s, Ar— 1575- (M +− 47) H) · 6.93(1 H, s, 1501- Ar—H)· 7.23(1 H, 1458 d, J = 8 Hz, Ar—H) · 7.33(1 H, s, Ar—H) · 7.44(1 H, d,J = 8 Hz, Ar—H) ·? (1 H, ?, OH) ·? (1 H, ?, OH)·

[0353] TABLE 15 Example melting point NMR No (centi degree) NMR solventIR Appearance Mass UV 143  37.9-41.5 1.15(3 H, t, J = CDCI3 3499- orange270(M+, Base) ε max 36839(λ max 7.6 Hz, CH3) · 3262- needle 219.2 nm)·2.75(2 H, br, CH2) · 1588 crystal 5.25(2 H, s, OH) · 6.73(1 H, s, Ar—H)6.88(1 H, s, Ar—H) · 7.00(1 H, s, Ar—H) · 7.21-7.29(2 H, m, Ar—H) ·7.37(1 H, d, J = 7.5 Hz, Ar—H) · 7.51(1 H, d, J = 7.1 Hz, Ar—H) 1440.99(3 H, t, J = CDCI3 3379- orange 272(M+, Base) ε max 8392(λ 7.2 Hz,CH3) · 2962- oil max 273.6 nm) · ε 1.62-1.73(2 H, 2932- max 45531(λ maxm, CH2) · 3.08(1 H, 2873- 205.2 nm) · dd, J = 14.8, 1598- 10.3 Hz, CH2)· 1504 3.25(1 H, dd, J = 14.8, 3.6 Hz, CH2) · 3.42(1 H, m, CH) · 5.24(1H, brs, OH) · 5.32(1 H, brs, OH) · 6.71(1 H, s, Ar—H) 6.98(1 H, s, Ar—H)· 7.04(1 H, t, J = 7.2 Hz, Ar—H) · 7.12(1 H, d, J = 7.13 Hz, Ar—H) ·7.17(1 H, t, J = 7.6 145  68.2-70.1 2.40(3 H, s, CH3) · CDCI3 3393-orange 256(M+, Base) ε max 19345(λ max 5.31(1 H, s, OH) · 3216- needle265.6 nm) · ε max 6.71(1 H, s, Ar—H) · 1589 crystal 39937(λ max 6.92(1H, s, Ar—H) · 219.2 nm)· 7.00(1 H, s, Ar—H) · 7.24-7.29(3 H, m, Ar—H) ·7.38(1 H, d, J = 1.5 Hz, Ar—H) · 7.50(1 H, d, J = Hz, Ar—H) · 146 (3 H,t, J = CDCI3 3369- pale yellow 258(M+, Base) λ max nm(ε) · Hz, CH3) ·2.98(1 H, 2962- oil 206.0(47400)-273.2 dd, J = 14.8, 2927- (8700) 9.8Hz, CH2) · 1598- 3.39(1 H, dd, J = 1506- 14.8, 3.9 Hz, CH2) · 1472 (1 H,q, CH) · 5.12(1 H, s, OH) · 5.24(1 H, s, OH) · 6.70(1 H, s, Ar—H) 7.00(1H, s, Ar—H) · 7.02-7.06(1 H, m, Ar—H) · 7.16(2 H, s, Ar—H) · 7.40(1 H,d, J = 7.6 Hz, Ar—H) 147 1.16(3 H, t, J = CDCI3 3213- pale red 254(M+,Base) λ max nm(ε) · 7.6 Hz, CH3) · 2962- oil 212.0(40800) · sh 2.77(2 H,d, J = 2926- 230(27300) · 263.6 6.6 Hz, CH2) · 2869- (20200) · 292.8(sh4.74(1 H, s, OH) · 1593 7000) 6.72(1 H, dd, J = 8.4, 2.4 Hz, CH) ·6.94(1 H, s, Ar—H) · 6.98(1 H, d, J = 2.3 Hz, Ar—H) · 7.09(1 H, d, J =8.4 Hz, Ar—H) 7.23(1 H, dd, J = 7.2, 0.9 Hz, Ar—H) · 7.29(1 H, td, J =7.1, 1.2 Hz, Ar—H) · 738(1 H, d, J = 7.7 Hz, Ar—H) · 7.52(1 H, dd, 1480.99(3 H, t, J = CDCI3 3360- colorless 256(M+)-213 λ max nm(ε) · 7.4 Hz,CH3) · 1.59- 2962- oil (Base) 203.6(31900) · 274.0 1.77(2 H, m, CH2) ·2931- (6800) 3.06(1 H, dd, J = 2873- 15.2, 10.2 Hz, CH2) · 1601- 3.29(1H, dd, J = 1493 15.2, 3.2 Hz, CH2) · 3.47(1 H, q, CH) · 4.62(1 H, s, OH)· 6.63(1 H, dd, J = 8.2, 2.6 Hz, Ar—H) · 6.94(1 H, d, J = 2.5 Hz, Ar—H)· 7.01(1 H, d, J = 8.3 Hz, Ar—H) · 7.07(1 H, td, J = 7.8, 7.8 Hz, Ar—H)7.15(1 H, d, J = 149 2.40(3 H, s, CH3) · COCI3 3369- redoil 240(M+,Base) ε max 17324(λ max 4.86(1 H, s, OH) · 1598- 264.4 nm) · ε max6.71(1 H, dd, J = 1489- 35918(λ max 8.4, 2.5 Hz, Ar—H) · 1473 208.0 nm)6.98(2 H, s, Ar—H) · 7.07(1 H, d, J = 8.4 Hz, Ar—H) · 7.23-7.31(2 H, m,Ar—H) · 7.4(1 H, dd, J = 7.7, 1.0 Hz, Ar—H) · 7.51(1 H, dd, J = 7.5, 0.9Hz, Ar—H) · 150 1.06(6 H, t, J = CDCI3 3491- 300(M+, ε max 19832(λ max7.5 Hz, CH3) · 3308- Base)- 266.8 nm) · ε max 2.51-2.56(1 H, 2978- 285-28582(λ max m, CH2) 2969- 267-254 239.6 nm) · ε max 3.31-3.15(1 H, 2933-44022(λ max m, CH2)5.39(2H, 2871- 206.0 nm)· brs, OH) · 2834- 6.99(1 H,s, Ar—H) 1608- 7.03(1 H, s, Ar—H) · 1584- 7.15-7.16(1 H, m, 1503- Ar—H)· 7.24- 7.26(1 H, m, Ar—H) · 7.37-7.38(1 H, m, Ar—H) · 7.47-7.48 (1 H,m, Ar—H)· 151 1.29(3 H, d, J = CDCI3 3361- colorless λ max nm(ε) · 7.0Hz, CH3) · 2962- oil 205.6(36500) · 272.4 2.98(1 H, dd, J = 2927- (8300)15.1, 9.9 Hz, CH2) · 2874- 3.38(1 H, dd, J = 1601- 15.1, 3.2 Hz, CH2) ·1494 3.72-3.78(1 H, m, CH) · 4.7(1 H, s, OH) · 6.64(1 H, dd, J = 8.4,2.6 Hz, Ar—H) · 6.96(1 H, d, J = 2.5 Hz, Ar—H) · 7(1 H, d, J = 8.3 Hz,Ar—H) · 7.05-7.10(1 H, m, Ar—H) · 7.19(2 H, d, J = 30 Hz, Ar—H) · 7.43(1H, d, J = 7.7 Hz, Ar—H) 152 0.98(3 H, t, J = CDCI3 + C 3372- 7.6 Hz,CH3) · 1.34- D3OD 3270- 1.42(2 H, m, CH2) · 2959- 1.95-2.05(1 H, m,2937- CH2) · 2.43-2.48 2873- (1 H, m, CH2) · 1647- 4.82(1 H, t, J =1595- 8 Hz, CH) · 7.06(1 H, 1582- s, Ar—H) · 1506- 7.14(1 H, t, J = 14628 Hz, Ar—H) · 7.33- 7.40(2H, m, Ar—H) · 7.58(1 H, s, Ar—H) · 7.65(1 H,d, J = 7.6 Hz, Ar—H) · 153 242.9-248.4 0.91(3 H, t, J = DMSO-d6 3504-orange 352(M+, λ max nm(ε) · 7.2 Hz, CH3) · 1.92- 3288- needle Base)-205.2(28400) · 244.4 2.01(1 H, m, CH2) · 2968- crystal 323 (24400)-260.02.33-2.43(1 H, m, 2935- (22500) · 280.4 CH2) · 4.61-4.65 2877- (21200) ·328.8(sh (1 H, m, CH) · 1645- 7500) 6.59-6.60(1 H, m, 1596- Furyl-H) ·6.98(1 H, 1503- s, Ar—H) · 1465 7.04(1 H, d, J = 3.3 Hz, Furyl-H) ·7.39(1 H, d, J = 8.2 Hz, Ar—H) · 7.50(1 H, s, Ar—H) · 7.77(2 H, m, Ar—H,Furyl-H) · 8.01(1 H, s Ar—H) ·

[0354] TABLE 16 Example melting point NMR No (centi degree) NMR solventIR Appearance Mass UV 154 274.3-276.1 0.99(3 H, t, J = DMSO-d6 3480-orange 362(M+, Base) λ max nm(ε) · 7.2 Hz, CH3) · 2.01- 3343- amorphous204.4(54900) · 246.4 2.08(1 H, m, CH2) · 1645- (37300) · 260.82.39-2.51(1 H, 1600- (40400) · 3324 m, CH2) · 1508 (6200) 4.72(1 H, t, J= 7.0 Hz, CH) · 7.04 (1 H, s, Ar—H) · 7.44(1 H, t, J = 7.2 Hz, Ar—H) ·7.5 K3H, q, J = 7.6 Hz, Ar—H) · 7.57(1 H, s, Ar—H) · 7.73(2 H, d, J =7.5 Hz, Ar—H) · 7.81(1 H, dd, J = 8.1, 1.4 Hz, Ar—H) · 8.02(1 H, d, J =1.4 Hz, Ar—H) · 155 270.3-271.9 0.98(3 H, t, J = DMSO-d6 3509-

needle 368(M+, λ max nm(ε) · 7.2 Hz, CH3) · 1.98- 3282- crystal Base)-205.6(30200) · 246.4 2.05(1 H, m, CH2) · 2974- 335- (28900) · 260(sh2.41-2.49(1 H, 2934- 24700) · 285.2(25800) m, CH2) · 4.69(1 H, 2875- t,J = 7.1 Hz, 1645- CH) · 7.04(1 H, s, 1597- Ar—H) · 1506 7.2(1 H, dd, J =4.7, 4.0 Hz, Ar—H) · 7.43(1 H, d, J = 8.2 Hz, Ar—H) · 7.57(1 H, s, Ar—H)· 7.63(2 H, dd, J = 2.6, 2.5 Hz, Ar—H) · 7.78(1 H, dd, J = 8.1, 1.5 Hz,Ar—H) · 8.02(1 H, d, J = 1.6 Hz, Ar—H) · ·· 156 109.7-111.9 1.03(3 H, t,J = CDCI3 3325- pale yellow 430(M+, base) λ max nm(ε) · 7.2 Hz, CH3) ·2.08- 2970- needle 334.8(4800) · 260.4 2.15(1 H, m, CH2) · 2939- crystal(36100) · 248.4(sh 2.49-2.56(1 H, m, 2879- 31600) · 205.6(43800) CH2) ·4.79(1 H, t, 1649- J = 7.2 Hz, CH) · 1602- 6.03(1 H, s, OH) · 1507-7.16(1 H, s, Ar—H) · 1336 7.22(1 H, s, OH) · 7.42(1 H, d, J = 8.1 Hz,Ar—H) · 7.54(1 H, t, J = 7.8 Hz, Ar—H) · 7.60-7.62(2 H, m, Ar—H) ·7.71(1 H, d, J = 7.6 Hz, Ar—H) · 7.78((H, s, CH) · 7.91(1 H, d, J = 1.5Hz, A 157 175.5-176.8 1.03(3 H, t, J = CDCI3 3494- pale yellow 396 (M+,λ max nm(ε) · 7.5 Hz, CH3) · 2.07- 3302- amorphous Base)- 334.4(6200) ·260.8 2.14(1 H, m, CH2) · 2967- 363- (41000) · 246.4(sh 2.49-2.56(1H, m,2936- 35500) · 209.2(49700) CH2) · 4.77(1 H, t, 2877- J = 6.8 Hz, CH) ·1646- 7.14(1 H, s, Ar—H) · 1595- 7.31-7.42(4 H, m, 1581- Ar—H) · 7.52(1H, 1508- s, Ar—H) · 758(1 H, 1466 d, J = 8.1 Hz, Ar—H) · 7.87(1 H, d, J= 1.6 Hz, Ar—H) · 7.95(1 H, s, Ar—H) · 158 179.2-181.1 1.00(3 H, t, J =DMSO-d6 3511- dark red 376(M+, λ max nm(ε) · 7.2 Hz, CH3) · 2.00- 3293-amorphous Base) 337.2(5300) · 290 2.07(1 H, m, CH2) · 2970- (sh 11200) ·258.4 2.26(3 H, s, Ar—CH3) · 2935- (31000) · 244.4 2.46- 2877- (32500) ·207.6(46600) 2.54(1 H, m, CH2) · 1645- 4.68-4.72(1 H, m, 1599- CH) ·7.03(1 H, s, 1507- Ar—H) · 7.24- 1455 7.34(4H, m, Ar—H) · 7.46(1 H, d, J= 8.1 Hz, Ar—H) · 7.51(1 H, dd, J = 8.1, 1.2 Hz, Ar—H) · 7.58(1 H, s,Ar— H) · 7.70(1 H, d, J = 1.2 Hz, CH) · 9.65(1 H, s, OH) · 10.26(1 H, s,OH 159 238.7-241.7 3.04(2 H, q, J = DMSO-d6 3478- 352 λ max nm(ε) · 4.1Hz, CH2) · 3430- (M+, Base), 301.6(33200) · 286 3.29(2 H, q, J = 2974-295- (sh 31400) · 239.6 3.9 Hz, CH2) · 1644- 319- (25800) · 204.4(33600)6.31(1 H, d, J = 1600- 2.3 Hz, Ar—H) · 1500 6.39(1 H, d, J = 2.4 Hz,Ar—H) · 6.64(1 H, dd, J = 3.6, 1.7 Hz, Ar—H) · 7.03(1 H, d, J = 3.1 Hz,Ar—H) · 7.36(3 H, d, J = 8.0 Hz, Ar—H) · 7.62(1 H, dd, J = 7.6, 1.8 Hz,Ar—H) · 7.79(2 H, d, J = 1.7 Hz, Ar—H) · 9.3(1 H, s, OH) · 9.53(1 H, s,OH) 160 271.9-273.3 0.99(3 H, t, J = DMSO-d6 3494- orange 376(M+, λ maxnm(ε) · 7.2 Hz, CH3) · 2.02- 3315- needle Base) 262.4(40933) · 245.62.05(1 H, m, CH2) · 2970- crystal (37746) · 204.4(63180) 2.39(3 H, s,CH3) · 2878- 2.45-2.48(1 H, m, 1645- CH2) · 4.70(1 H, t, 1599- J = 7.2Hz, CH) · 1505 7.04(1 H, s Ar—H) · 7.32(2 H, d, J = 7.9 Hz, Ar—H) ·7.46(1 H, d, J = 8.2 Hz, Ar—H) · 7.57(1 H, s, Ar—H) · 7.63(2 H, d, J =8.0 Hz, Ar—H) · 7.79(1 H, d, J = 8.0 Hz, Ar—H) · 7.99(1 H, d, J = 1.0Hz, Ar—H) · 9.9 161 277.4-279.2 0.94(3 H, t, J = DMSO-d6 3509- needle402 λ max nm(ε) · 336 7.4 Hz, CH3) · 3288- crystal (M+, Base) (sh 33900)· 318.8 2.04(2 H, m, CH2) · 2965- (46200) · 241.2 4.66(1 H, t, J = 2874-(30200) · 207.6(46100) 6.0 Hz, CH) · 1647- 6.97(1 H, s, Ar—H) · 1597-7.27-7.34(2 H, m, 1506- Ar—H) · 7.51(1 H, 1450 s, Ar—H) · 7.61-7.67(3 H,m, Ar—H) · 7.78- 7.82(3 H, m, Ar—H) · 9.62(1 H, brs, OH) · 10.09(1 H,brs, OH) 162 225.7-227.4 3507- needle λ max nm(ε) 3282- crystal 1645-1598- 1583- 1502 163 225.7-227.3 needle λ max nm(ε) crystal

[0355] TABLE 17 Example melting point NMR No (centi degree) NMR solventIR Appearance Mass UV 166 0.90(3 H, t, J = DMSO-d6 ε max 6269(λ max 7.2Hz, CH3) · 1.91- 338.8 nm) · ε max 1.97(1 H, m, CH2) · 23173(λ max2.35-2.41(1 H, 257.6 nm) · ε max m, CH2) · 4.61(1 H, 23680(λ max t, J =7.2 Hz, 243.6 nm) · CH) · 6.96(1 H, s, Ar—H) · 7.23(1 H, t, J = 7.6 Hz,Ar—H) · 7.35(1 H, d, J = 7.7 Hz, Ar—H) · 7.45- 7.49(2 H, m, Ar—H) ·7.70(1 H, d, J = 7.6 Hz, Ar—H) 167 0.90(3 H, t, J = DMSO-d6 ε max 6426(λmax 7.2 Hz, CH3) · 1.92- 339.2 nm) · ε max 1.95(1 H, m, CH2) · 23731(λmax 2.36-2.41(1 H, 257.6 nm) · ε max m, CH2) · 4.61(1 H, 24247(λ max t,J = 7.2 Hz, 243.6 nm)· CH) · 6.96(1 H, s, Ar—H) · 7.23(1 H, t, J = 7.2Hz, Ar—H) · 7.35(1 H, d, J = 7.7 Hz, Ar—H) · 7.45- 7.49(2 H, m, Ar—H) ·7.70(1 H, d, J = 7.6 Hz, Ar—H) · 168 293.2(decom- 0.99(3 H, t, J =DMSO-d6 pale yellow 402(M+, λ max nm(ε) · position) 7.2 Hz, CH3) · 2.01-amorphous Base) 310.4(32461) · 245.6 2.08(1 H, m, CH2) · (31228) ·206.4(48450) 2.45-2.2, 52(1 H, m, CH2) · 4.75(1 H, t J = 7.2 Hz, CH) ·7.07(1 H, s, Ar—H) · 7.33(1 H, t, J = 7.6 Hz, ) · 7.40(1 H, t, J = 7.6Hz, ) · 7.54(1 H, d, J = 8.3 Hz, Ar—H) · 7.58(1 H, s, Ar—H) · 7.59(1 H,s, Ar—H) · 7.69(1 H, d, J = 8.2 Hz, Ar—H) · 7.72(1 H, d, J = 7.6 Hz,Ar—H) · 8.05(1 H, 169 216.8-219.1 0.99(3 H, t, J = DMSO-d6 pale brown446(M+, λ max nm(ε) · 7.4 Hz, CH3) · 2.01- needle Base) 260.4(36913) ·245.2 2.08(1 H, m, CH2) · crystal (35410) · 204.0(59710) 2.39-2.51(1 H,m, CH2) · 4.72(1 H, t, J = 7.2 Hz, CH) · 7.05(1 H, s, Ar—H) ·7.49-7.51(3 H, m, Ar—H) · 7.57(1 H, s, Ar—H) · 7.82-7.84(1 H, m, Ar—H) ·7.86-7.88 (2 H, m, Ar—H) · 8.06(1 H, s, Ar—H) · 10.04(2 H, brs, OH)170 >312(decom- 0.99(3 H, t, J = DMSO-d6 brown 446(M+, λ max nm(ε) ·position) 7.2 Hz, CH3) · 2.01- amorphous Base) 302.8(21641)·209.6 2.08(1H, m, CH2) · (44871) 2.44-2.51(1 H, m, CH2) · 4.73(1 H, t, J = 7.2 Hz,CH) · 7.07 (1 H, s, Ar—H) · 7.41-7.52(3 H, m, Ar—H) · 7.58(1 H, s, Ar—H)· 7.90(2 H, d, J = 7.9 Hz, Ar—H) · 8.01-8.05(2 H, m, Ar—H) · 8.16(1 H,s, Ar—H) · 9.68(1 H, s, OH) · 10.30(1 H, s, OH) 171 >300 1.0(3 H, t, J =DMSO-d6 pinkish-white 438(M+, λ max nm(ε) · 6.8 Hz, CH3) · 2.04-amorphous Base) 279.6(33361) · 245.6 2.07(1 H, m, CH2) · (25555) ·205.6(59442) 2.45-2.52(1 H, m, CH2) · 4.73(1 H, t, J = 7.2 Hz, CH) ·7.06(1 H, s, Ar—H) · 7.42-7.56(4 H, m, Ar—H) · 7.58(1 H, s, Ar—H) ·7.77-7.89(7 H, m, Ar—H) · 8.09(1 H, s, Ar—H) 172 251.4- 0.94(3 H, t, J =DMSO-d6 pinkish-white 418(M+, λ max nm(ε) · 255.5(decom- 7.2 Hz, CH3) ·1.98- amorphous Base)- 233.2(38900) · 250.0 position) 2.07(2 H, m, CH2)· 361-385 (33300) · 312.0 4.66(1 H, t, J = (29900) · 340.0(21700) 7.1Hz, CH) · 6.96(1 H, s, Ar—H) · 7.35-7.40(2 H, m, Ar—H) · 7.51(1 H, s,Ar—H) · 7.60- 7.66(2 H, m, Ar—H) · 7.77(1 H, d, J = 8 Hz, Ar—H) · 7.85(1H, d, J = 8 Hz, Ar—H) · 7.97-8.01(2 H, m, Ar—H) · 9.68(1 H, s, OH) ·10.30(1 H, s, OH) 173 0.92(3 H, t, J = DMSO-d6 pale brown oil 394(M+,7.2 Hz, CH3) · 1.94- Base) 1.99(1 H, m, CH2) · 2.37-2.41(1 H, m, CH2) ·4.61(1 H, t, J = 7.1 Hz, CH) · 6.79(1 H, d, J = 8.1 Hz, Ar—H) · 6.94(1H,dd, J = 8.1, 1.8 Hz, Ar—H) · 6.98(1 H, s, Ar— H) · 7.01(1 H, d, J = 1.8Hz, Ar—H) · 7.35(1 H, d, J = 8.1 Hz, Ar—H) · 7.50(1 H, s, Ar—H) · 7.60(1H, dd, J = 8.1, 1.3 Hz, Ar—H) · 7.79(1 H, 174 0.92(3 H, t, J = DMSO-d6pale orange 394(M+, 7.2 Hz, CH3) · 1.94— oil Base) 1.99(1 H, m, CH2) ·2.35-2.42(1 H, m, CH2) · 4.60(1 H, t, J = 7.2 Hz, CH) · 6.29(1 H, dd, J= 8.4, 2.0 Hz, Ar—H) · 6.39(1 H, d, J = 2.0 Hz, Ar—H) · 6.96(1 H, s,Ar—H) · 7.06(1 H, d, J = 8.3 Hz, Ar—H) · 7.30(1 H, d, J = 8.1 Hz, Ar—H)· 7.50(1 H, s, Ar—H) · 7.56(1 H, d, J = 8.1 Hz, Ar—H) · 7.79(1 H, s, Ar—175 221.8-225.0 0.94(3 H, t, J = DMSO-d6 yellow 407(M+, λ max nm(ε) ·7.2 Hz, CH3) · 1.98- needle Base) 260.4(52815) · 2.01(1 H, m, CH2) ·crystal 2.39-2.47(1 H, m, CH2) · 4.69(1 H, t, J = 7.2 Hz, CH) · 7.01(1H, s, Ar—H) · 7.48(1 H, d, J = 8.2 Hz, Ar—H) · 7.53(1 H, s, Ar—H) ·7.75(1 H, t, J = 8 Hz, Ar—H) · 7.87(1 H, dd, J = 8.1, 9 Hz, Ar—H) ·8.11(1 H, d, J = 1.9 Hz, Ar—H) · 8.16(1 H, d, J = 7.7 Hz, Ar—H) ·8.21-8.23(1 H, m, Ar 176 245.5-246.4 0.93(3 H, t, J = DMSO-d6pinkish-white 377(M+, λ max nm(ε) · 7.2 Hz, CH3) · 1.95- amorphous Base)243.2(43705) · 206.4 1.99(1H, m, CH2) · (49928) 2.39-2.42(1 H, m, CH2) ·4.62- 4.65(1 H, m, CH) · 5.15(2 H, s, NH2) · 6.56(1 H, dd, J = 7.9, 1.6Hz, Ar—H) · 6.77(1 H, d, J = 7.8 Hz, Ar—H) · 6.84(1 H, d, J = 1.6 Hz,Ar—H) · 6.98(1 H, s, Ar—H) · 7.08(1 H, dd, J = 7.9, 7.8 Hz, Ar—H) ·7.39(1 H, d, J = 8.2 Hz, Ar—H) · 7.51(1 H, s, Ar

[0356] TABLE 18 Example melting point NMR No (centi degree) NMR solventIR Appearance Mass UV 177 155.4-159.4 0.93(3 H, t, J = DMSO-d6pinkish-white 378(M+, 7.2 Hz, CH3) · 1.95- needle Base) 1.99(1 H, m,CH2) · crystal 2.38-2.41(1 H, m, CH2) · 4.60- 4.64(1 H, m, CH) · 6.83(2H, d, J = 9.3 Hz, Ar—H) · 6.70(1 H, s, Ar—H) · 7.36(1 H, d, J = 8.2 Hz,Ar—H) · 7.50(3 H, d, J = 9.3 Hz, Ar—H) · 7.66(1 H, dd, J = 8.2, 1.9 Hz,Ar—H) · 7.86(1 H, d, J = 1.9 Hz, Ar—H) · 178 1.00(3 H, t, J = CDCI3colorless 300(M+, 7.2 Hz, CH3) · 2.03- needle Base)- 2.06(1 H, m, CH2) ·crystal 285 2.53-2.57(1 H, m, CH2) · 3.97(3 H, s, OCH3) · 4.71-4.74(1 H,m, CH) · 5.54(1 H, s, OH) · 7.01(1 H, s, Ar—H) · 7.13-7.16(1 H, m, Ar—H)· 7.34- 7.41(2 H, m, Ar—H) · 7.65(1 H, d, J = 7.6 Hz, Ar—H) · 7.76(1 H,s, Ar—H) · - 179 1.01(3 H, t, J = CDCI3 pale orange 300(M+, 7.2 Hz, CH3)· 202- needle Base)- 2.09(1 H, m, CH2) · crystal 285 2.51-2.58(1 H, m,CH2) · 3.89(3 H, s, OCH3) · 4.70-4.73(1 H, m, CH) · 6.08(1 H, s, OH) ·7.12(1 H, s, Ar—H) · 7.14- 7.16(1 H, m, Ar—H) · 7.33-7.41(2H, m, Ar—H) ·7.65(1 H, d, J = 7.7 Hz, Ar—H) · 7.71(1 H, s, Ar—H)· 180 0.90(3 H, t, J= DMSO-d6 UV I max: 7.3 Hz, CH3) · 244 nm(e 25,100), 1.97(1 H, m,272(12,700), 337 CH2CH3) · 2.42(1 H, (4,000) m, CH2CH3). 3.3-3.5 (7 H,m, Glu-H) · 4.03(1 H, m, Glu-H), 4.61(1 H, m, 11-H) · 5.29(0.5 H, d, J =7.3 Hz, anomeric) · 5.18(0.5 H, d, J = 7.3 Hz, anomeric) · 7.2-7.8(6 H,m, aromatic)

Example 164

[0357] Preparation of11-Ethyl-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one (Compoundof Example 4)

[0358] Synthesis of Carboxylic Acid (67)

[0359] A mixture of 39.3 g (F.W. 154.19, 255 mmol) of thiosalicylic acid(65), 55.4 g (F.W. 217.06, 255 mmol) of 4-bromoveratrole, 1.90 g (F.W.63.55, 30.0 mmol) of copper (powder), 5.7 g (F.W. 190.45, 30.0 mmol) ofcopper (I) iodide, 45.0 g (F.W. 138.21, 326 mmol) of potassium carbonateand 120 mL of N-methyl-2-pyrrolidone was stirred at 150° C. for fourhours. After the reaction, the reaction solution was cooled by standingto 70 to 80° C., and ice water was added thereto and the resultingsolution was made pH 2 with hydrochloric acid. The deposited crudecrystals were collected by filtration, washed with water, diisopropylether and hexane in the order named and dried to obtain 74.4 g of acrude product. This product was recrystallized from 1,4-dioxane toobtain 55 g of carboxylic acid (67). Ethyl acetate was added to thecrude carboxylic acid obtained by concentrating the mother liquor, andthe resulting solution was filtered and then, the residue was washedwith ethyl acetate to obtain 6.1 g (total yield 83%) of carboxylic acid(67).

[0360] Synthesis of Alcohol (68)

[0361] To a solution of 75.2 g (F.W. 290.34, 259 mmol) of carboxylicacid (67) in 200 mL of tetrahydrofuran, 10.4 g (F.W. 37.83, 274 mmol) ofsodium borohydride was added at 0° C. and then, 37.0 mL (F.W. 141.93,d=1.154, 301 mmol) of boron trifluoride diethyl etherate was addeddropwise thereto at the same temperature, and the resulting solution wasstirred at room temperature for one hour. To this reaction solution wasslowly added ice water and the resulting solution was extracted withethyl acetate and the extract was washed with water and then with asaturated sodium chloride aqueous solution. The obtained reactionsolution was dried with anhydrous magnesium sulfate and then, thesolvent was removed under reduced pressure to obtain 73.4 g of crudealcohol (68).

[0362] Synthesis of Bromide (69)

[0363] To a solution of 73.4 g (F.W. 276.36) of crude alcohol (68) in100 mL of methylene chloride, 8.5 mL (F.W. 270.70, d=2.850, 89.0 mmol)of phosphorus tribromide was added at 0° C. After stirring at roomtemperature for 30 minutes, this reaction solution was added ontocrushed ice. The solution was further stirred at room temperature for 30minutes and then, water was added thereto and the resulting solution wasextracted with methylene chloride and the extract was washed with waterand a saturated sodium chloride aqueous solution. The obtained solutionwas dried with anhydrous magnesium sulfate and then, the solvent wasremoved under reduced pressure. As the result, 83.4 g of a crude productwas obtained. This crude bromide was recrystallized from methylenechloride-hexane to obtain 75.2 g of bromide (69). The yield was 86% intwo steps.

[0364] Synthesis of Nitrile Compound (70)

[0365] To 15 mL of water was dissolved 1.76 g (F.W. 49.01, 36.0 mmol) ofsodium cyanide and then, 20 mL of ethanol was added thereto. To theresulting solution was slowly added 10.2 g (F.W. 339.25, 30.0 mmol) ofbromide (69) at room temperature. This mixed solution was heated to 80°C. and stirred at the same temperature for 30 minutes. This reactionsolution was cooled by standing to room temperature while vigorouslystirring. Ethanol was removed under reduced pressure and water was addedto the remaining solution. The deposited crude crystals were collectedby filtration and washed with water. After drying, 8.13 g of a crudenitrile compound was obtained. These crude crystals were recrystallizedfrom ethyl acetate-hexane to obtain 7.30 g (yield 85.3%) of nitrilecompound (70).

[0366] Synthesis of Ethylated Compound (71)

[0367] To a solution of 22.8 g (F.W. 285.37, 80.0 mmol) of nitrilecompound (70) in 50 mL of methylene chloride was added dropwise 6.72 mL(F.W. 155.95, d=1.94, 84.0 mmol) of ethyl iodide and stirred.Furthermore, 27,2 g (F.W. 339.54, 80.0 mmol) of tetrabutylammoniumhydrogen sulfate was added thereto to completely dissolve nitrilecompound (70). To this solution was added dropwise a 20% sodiumhydroxide aqueous solution (80 g) and then, stirred at room temperaturefor one hour. Under cooling with ice, the reaction was neutralized byaddition of 4N hydrochloric acid and then, extracted with methylenechloride and the organic layer was washed with water and a saturatedsodium chloride aqueous solution. The obtained solution was dried withanhydrous magnesium sulfate and then, the solvent was removed underreduced pressure to obtain an oily product. To the residue was added a3:1=hexane:ethyl acetate mixture to remove tetrabutylammonium iodidedeposited by filtration. The filtrate was removed under reduced pressureto obtain 27.0 g of crude ethylated compound (71).

[0368] Synthesis of Phenylacetic Acid (72)

[0369] To a mixture of 27.0 g (F.W. 313.41, 77.2 mmol) of crudeethylated compound (71) and 66 mL of ethylene glycol was added a 30%sodium hydroxide aqueous solution (42.7 g). The resulting solution wasstirred at 150° C. overnight. To the reaction solution was added ice andthe resulting solution was neutralized with 4N hydrochloric acid. Theneutralized solution was extracted with ethyl acetate and the extractwas washed with water and then with a saturated sodium chloride aqueoussolution. The obtained solution was dried with anhydrous magnesiumsulfate and then, the solvent was completely removed under reducedpressure to obtain 29.0 g of crude phenylacetic acid (72). This crudephenyacetic acid was recrystallized from ethyl acetate-hexane to,obtain23.0 g of phenylacetic acid (72). The yield was 87% in two steps.

[0370] Synthesis of Cyclized Compound (51)

[0371] To 10.0 g (F.W. 332.41, 30.1 mmol) of dried phenylacetic acid(72) was added 50 mL of methanesulfonic acid to dissolve phenylaceticacid (72) and then, stirred at room temperature overnight. To thereaction solution was added water under cooling with ice and then, theresulting solution was partitioned with ethyl acetate and water, and theorganic layer was washed with water and then with a saturated sodiumchloride aqueous solution. The obtained solution was dried withanhydrous sodium sulfate and then, the solvent was removed under reducedpressure to obtain 9.52 g of a crude product. A small amount of ethylacetate was added to this crude product which was then collected byfiltration then, the residue was washed with a small amount of ethylacetate to obtain 8.84 g (yield 93.4%) of cyclized compound (52).

[0372] To 25.0 g (F.W. 314.40, 80.0 mmol) of cyclized compound (51) wasadded 150 g of pyridine hydrochloride and stirred at 200° C. for twohours. To the reaction mixture was added diluted hydrochloric acid andethyl acetate and the resulting solution was extracted, and the organiclayer was washed with water and then with a saturated sodium chlorideaqueous solution and dried with anhydrous magnesium sulfate. Theconcentrated residue was dissolved in 800 mL of ethyl acetate and polarsubstances were adsorbed on 50 g silica gel and 25 g of Florisil andthen, filtered. Ethyl acetate in the filtrate was concentrated and then,the residue was recrystallized from ethyl acetate-hexane to obtain 19.9g (yield 87%) of the title compound.

Example 165

[0373] Preparation of11-Ethyl-7,9-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one (Compoundof Example 4)

[0374] Synthesis of Ethylated Compound (74)

[0375] To a solution of 30.0 g (F.W. 196.05, 153 mmol) of nitrilecompound (73) and 13.6 mL (F.W. 155.97, d=1.94, 169 mmol) of ethyliodide in 50 mL of toluene was quickly added a suspension of 51.8 g(F.W. 339.54, 153 mmol) of tetrabutylammonium hydrogen sulfate and a 20%sodium hydroxide aqueous solution (300 g) on an ice bath and stirred atroom temperature for two hours. The crystals of tetrabutylammoniumiodide produced were separated by filtration and the crystals werewashed with 200 mL of toluene. The organic layer was washed with waterand then with a saturated sodium chloride aqueous solution and driedwith anhydrous magnesium sulfate. The solvent was removed under reducedpressure to obtain 34.4 g of ethylated compound (74).

[0376] Synthesis of Carboxylic Acid (75)

[0377] To 34.4 g (F.W. 224.10) of ethylated compound (74) were added a6N sodium hydroxide aqueous solution (75.0 mL) and 75.0 mL of ethanoland stirred at 100° C. for two days. Ethanol was removed under reducedpressure and then, to the resulting solution was added toluene to effectpartition. To the aqueous layer was added concentrated hydrochloric acidand the resulting solution was made pH 3. The solution thus obtained wasextracted with ethyl acetate and washed with water and then with asaturated sodium chloride aqueous solution. After drying with anhydrousmagnesium sulfate, the solvent was removed under reduced pressure toobtain about 38 g of a crude product. This crude product wasrecrystallized from hexane to obtain 33.5 g of carboxylic acid (75). Theyield was 90% in two steps.

[0378] Synthesis of Phenylacetic Acid (72)

[0379] A mixture of 26.7 g (F.W. 243.10, 110 mmol) of carboxylic acid(75), 18.7 g (F.W. 170.23, 110 mmol) of 3,4-dimethoxythiophenol (76),3.50 g (F.W. 63.55, 55.0 mmol) of copper (powder), 10.5 g (F.W. 190.45,55.0 mmol) of copper (I) iodide, 18.2 g (F.W. 138.21, 132 mmol) ofpotassium carbonate and 140 mL of N-methyl-2-pyrrolidone was stirred at140° C. for 3.5 hours. To the reaction solution was added ice and theresulting solution was made pH 6 to 7 with concentrated hydrochloricacid under cooling with ice. Toluene and water were added thereto todissolve the product, and insolubles were separated by filtration. Tothe filtrate was added a 20% sodium hydroxide aqueous solution to effectpartition. The organic layer was separated and further extracted with a2% sodium hydroxide aqueous solution and then, combined with the aqueouslayer and made pH 2 to 3 with concentrated hydrochloric acid undercooling with ice. The obtained solution was extracted with ethyl acetateand the organic layer was washed with water, and dried with anhydroussodium sulfate and then, the solvent was removed under reduced pressureto obtain 35.1 g of a crude product. This product was washed with asmall amount of diisopropyl ether and then, dried to obtain 28.7 g(yield 78.6%) of phenylacetic acid (72).

[0380] Synthesis of Cyclized Compound (51)

[0381] To 28.6 g (F.W. 332.41, 86.0 mmol) of dried phenylacetic acidcompound (72) was added 140 mL of methanesulfonic acid and stirred atroom temperature overnight. The reaction solution was added dropwise toice water and the deposit was collected by filtration and then, washedwith water. After drying, 26.9 g (yield 99.4%) of cyclized compound (51)was obtained.

[0382] To 18.9 g (F.W. 314.40, 60.0 mmol) of cyclized compound (51) wasadded 56.6 g of pyridine hydrochloride and stirred at 185° C. for sixhours. The reaction mixture was completely cooled to room temperatureand then, ice water and ethyl acetate were added thereto and theresulting solution was extracted therewith. The organic layer was washedwith water and a saturated sodium chloride aqueous solution,subsequently dried with anhydrous sodium sulfate, and the solvent wasremoved under reduced pressure to obtain 16.2 g of a crude product. Thiscrude product was recrystallized from 60% isopropyl alcohol to obtain15.9 g (yield 92.4%) of the title compound.

Example 166

[0383] Preparation of(+)-11-Ethyl-7,9-dihydroxy-10,11-dihydrobenzo[b,f]thiepin-10-one[Optical Isomer (+) of

Compound of Example 4]

[0384] Compound of Example 4 was subjected to optical resolution by acolumn under the conditions as described below to obtain a frontal peak.This compound had a specific rotation [α]_(D) (200C) of +16.7.

[0385] Column: CHIRALPAK AD

[0386] Mobile Phase: n-hexane/ethanol/acetic acid=40/60/0.1 (vol/vol)

Example 167

[0387] Preparation of(−)-11-Ethyl-7,9-dihydroxy-10,11-dihydrobenzo[b,f]thiepin-10-one[Optical Isomer (−) of Compound of Example 4]

[0388] Compound of Example 4 was subjected to optical resolution by acolumn under the conditions as described below to obtain a rear peak.This compound had a specific rotation [α]_(D) (20° C.) of −16.7.

[0389] Column: CHIRALPAK AD

[0390] Mobile Phase: n-hexane/ethanol/acetic acid=40/60/0.1 (vol/vol)

Example 178

[0391] Preparation of a-Ethyl-2-bromophenylacetic Acid (75)

[0392] It was confirmed that the title compound obtained by the samemethod as described in Example 165 of up to the second step had thefollowing properties. Description: Colorless plate crystals

[0393] Melting Point: 37-39° C. (cold hexane)

[0394]¹H NMR (400 MHz, CDCl₃) δ: 0.94 (3H, dd, J=7.4, 7.4 Hz), 1.83 (1H,ddq, J=14.9, 7.4, 7.4 Hz), 2.10 (1H, ddq, J=14.9, 7.4, 7.4 Hz), 4.14(1H, dd, J=7.4, 7.4 Hz), 7.12 (1H, ddd, J=8.0. 7.5, 1.6 Hz), 7.29 (1H,ddd, J=7.8, 7.5, 1.2 Hz), 6.94 (1H, dd, J=7.8, 1.2 Hz), 7.38 (1H, dd,J=8.0, 1.6 Hz)

[0395] EIMS m/z: 244, 242 (M+), 199, 197, 171, 169, 163

[0396] IR (KBr)cm⁻¹: 1705

[0397] UV λ_(max) (EtOH) nm (ε): 274 (40), 264 (300)

Example 179

[0398] Preparation of α-Ethyl-2-[(3,4-dimethoxyphenyl)thio]phenylaceticAcid (72)

[0399] It was confirmed that the title compound obtained by the samemethod as described in Example 164 of up to the sixth step and inExample 165 of up to the third step had the following properties.

[0400] Description: Light brown amorphous powder

[0401] Melting Point: 115.2-117.0° C. (Dec.)

[0402]¹H NMR (400 MHz, CDCl₃) δ: 0.92 (3H, dd, J=7.4, 7.4 Hz), 1.79 (1H,ddq, J=14.8, 7.4, 7.4 Hz), 2.12 (1H, ddq, J=14.8, 7.4, 7.4 Hz), 3.79(3H, s), 3.87 (3H, s), 4.33 (1H, dd, J=7.4, 7.4 Hz), 6.80 (1H, d, J=8.3Hz), 6.88 (1H, d, J=1.9 Hz), 6.94 (1H, dd, J=8.3, 1.9 Hz), 7.14-7.26(3H, m), 7.37 (1H, d, J=1.8, Hz)

[0403] EIMS m/z: 332 (M+, Base)

[0404] IR (KBr) cm⁻¹: 1705, 1585, 1504, 1442

[0405] UV λ_(max) (EtOH) nm (ε): 250 (15200), 283 (8000)

Example 180

[0406] To a mixture of 1.00 g (F.W. 286.37, 3.50 mmol) of the compoundof Example 4 and 1N NaOH (4 mL) was added 6 mL of acetone dissolving1.40 g (F.W. 397.2, 3.50 mmol) of methyl acetobromoglucuronate in smallportions at 0° C. and stirred at room temperature for six hours whileadjusting the pH to around 6 with 1N NaOH. After concentration, 20% NaOH(11.2 mL) was added to the concentrated solution and stirred at roomtemperature for 30 minutes. After cooling, to the obtained solution wasadded 5 mL of concentrated hydrochloric acid attentively and theresulting solution was made pH 2 to 3 with 1N hydrochloric acid anddesalted with a column packed with “HP-20”. The column was thoroughlywashed with water, and then, the desired fraction was eluted with 100%methanol. The starting material was removed from 2.57 g of the obtainedcrude product by silica gel chromatography (silica gel 8 g; eluent; 33%ethyl acetate:hexane→20% ethanol:ethyl acetate). After concentration,the obtained crude product was further purified by HPLC (detection; 280nm; mobile phase, 50% MeCN—H₂O containing 0.2% of AcOH). Theconcentrated oily substance was dissolved in dioxane and freeze-dried toobtain 463 mg (yield 36%) of the title compound.

TEST EXAMPLES

[0407] It will now be shown that the compounds of the present inventionhave excellent pharmacological activities with reference to TestExamples.

Test Example 1 Dilating Action on Contraction of Tracheal Smooth Muscles

[0408] With the use of pig tracheal muscles, the action of the compoundsof the present invention on contraction of tracheal muscles has beeninvestigated. The method refers to “Smooth Muscle Manual” (published byBun'eido Publishing Co.), pp.125-137. The trachea cartilage mucousmembrane and submucous tissue of a pig trachea were removed to prepare aspecimen of tracheal smooth muscles having a major diameter of about 10mm and aminor diameter of about 1.5 mm. This specimen was suspended in aMagnus tube which was aerated with a mixed gas of 95% of oxygen and 5%of carbon dioxide and contained nutrient solution at 37° C. and a loadof 0.8 g was applied to this specimen, and after the tension of thespecimen was stabilized, the nutrient solution was replaced with a highconcentration K⁺ solution (72.7 mM) to provoke K⁺ contraction. Theprocedure of replacing the solution in the Magnus tube with the nutrientsolution to wash the solution and provoking K⁺ contraction with the highconcentration K⁺ solution was repeated again until the contraction forcebecame constant. When the tension of the K⁺ contraction became constant,each of the compounds described in Table 19 (the structural formula ofComparative Example being described in the right side of the compound ofthe above described Example 163) was added to the high concentration K⁺solution as the test substance to measure the change in tension. Thetest substance was dissolved in dimethyl sulfoxide at a predeterminedconcentration and added to the high concentration K⁺ solution in such amanner that the final concentration came to 10 SM. Further, the finalconcentration of dimethyl sulfoxide added was made 0.3% or less. Thechange in tension was led to a strain pressure amplifier (“AP-621G”,manufactured by Nippon Koden Kogyo) through a FD pickup transducer(“TB-611T”, manufactured by Nippon Koden Kogyo) and recorded on arecorder (“R-64V”, manufactured by Rika Electric). When the tensionbefore replacement with the high concentration K⁺ solution was regardedas 0% and the last tension which was generated by the high concentrationK⁺ solution before the addition of a test substance was Reguarded as100%, the contraction force of the tracheal smooth muscle two hoursafter addition of a test substance was shown as relative percentage.Further in this instance, the contraction by the high concentration K⁺solution was approximately constant for at least two hours after thetension had been stabilized. The results are shown in Table 19. TABLE 19Relative Contraction Example No. Force (%) 1 0 4 2.7 17 0 27 1.4 37 7.582 22.4 110 10.9 124 30.3 Comparative 54.5 Example

Test Example 2

[0409] Inhibition of Immediate Asthmatic Response, Late AsthmaticResponse and Infiltration of Inflammatory Cells into Lung of Guinea Pigs

[0410] It is reported [Pepys, J. and Hutchcroft, B. J., Bronchialprovocation tests in etiologic diagnosis and Analysis of asthma, Am.Rev. Respir. Dis., 112, 829-859 (1975)] that when asthmatic patients areallowed to inhale an antigen, immediate asthmatic response (hereinafterreferred to as “IAR”) whose peak is 15 to 30 minutes after inhalation isprovoked and recovery from this response is within two hours; however,in 60% of the asthmatic patients late asthmatic response (hereinafterreferred to as “LAR”) appears 4 to 12 hours after the inhalation of theantigen. LAR is considerably prolonged and is similar to a naturalattack of asthma, particularly an attack of intractable asthma and thus,it is thought very important for the therapy of bronchial asthma toclarify the pathology. On the other hand, it is known that when theguinea pigs actively sensitized with an antigen are allowed to inhalethe antigen again, biphasic airway responses are caused. Accordingly, asthe animal model line of IAR and LAR which are recognized in the abovedescribed asthmatic patients, the asthmatic model using guinea pigs iswidely used in the evaluation of drugs for asthma and the like.Furthermore, it is known that in the IAR and LAR model of guinea pigs,when actively sensitized guinea pigs are exposed to an antigen,infiltration of inflammatory cells into the airway occurs together withthe biphasic airway contraction to cause various inflammatory disordersto airway tissues thereby. Therefore, the number of inflammatory cellsin the bronchoalveolar lavage fluid is widely used as the index for theinfiltration of inflammatory cells into the airway. Each of the abovedescribed actions in the IAR and LAR model of guinea pigs was examinedwith the compounds of the present invention.

[0411] Experimental Method

[0412] (1) Sensitization

[0413] Guinea pigs were allowed to inhale a 1% ovalbumin (“OVA”,sigma-Aldrich Co., U.S.A.) physiological saline for 10 minutes dailycontinuously for 8 days using of an ultrasonic nebulizer (“NE-U12”,Omron, Japan).

[0414] (2) Challenge

[0415] One week after the final sensitization, the guinea pigs wereallowed to inhale a 2% “OVA” physiological saline for 5 minutes using ofthe nebulizer. Twenty-four hours and one hour before challenge, theguinea pigs were dosed with metyrapone (10 mg/kg, Sigma-Aldrich Co.,U.S.A.) intravenously, and dosed with pyrilamine (10 mg/kg,Sigma-Aldrich Co., U.S.A.) intraperitoneally 30 minutes beforechallenge.

[0416] (3) Preparation of Test Substance and Method of Administration

[0417] Each of the test substances (Compounds of Examples 1 and 4) wasformed into a suspension with a 0.5% carboxymethyl cellulose sodium salt(hereinafter referred to as “CMC-Na”) solution at a concentration of 2mg/mL. One hour before challenge, the guinea pigs were orally dosed withthe suspension of the test substance with such a dose so as to be 10mg/kg. For the control group the medium (a 0.5% CMC-Na solution) wasused.

[0418] (4) Measurement of Airway Resistance

[0419] The specific airway resistance (hereinafter referred to as“sRaw”) was measured, 1 minute, 10 minutes and 30 minutes afterchallenge and furthermore, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6hours, 7 hours, 8 hours and 24 hours, each time for the duration of 1minute with the use of airway resistance measuring equipment(“Pulmos-1”, M.I.P.S., Japan).

[0420] (5) Measurement of Number of Inflammatory Cells inBroncho-Alveolar Lavage Fluid

[0421] Twenty-three to twenty-four hours after the antigen challenge,the abdominal aorta of the guinea pigs was cut under intraperitonealanesthesia with “Nembutal” (50 mg/kg) to remove blood and the chest wasopened. A tube was inserted in the bronchus and fixed thereto andthrough this tube, 5 mL (37° C.) of a physiological saline was injectedand sucked therethrough; this procedure was repeated twice (10 mL intotal) and the recovered fluid was regarded as the bronchoalveolarlavage fluid (hereinafter referred to as “BALF”). BALF was centrifugedat 1,100 rmp at 4° C. for 10 minutes to obtain a precipitate (a pellet).This pellet was suspended in 1 mL of a physiological saline and aTurkllquid was added thereto and the number of leukocytes per FL wascounted with a leukocyte counter plate. Centrifugation was repeatedunder the above described conditions and rabbit serum was added to theobtained pellet to prepare a smear preparation. After drying, thepreparation was subjected to the May Grunwald-Giemsa stain. The numberof leukocytes was counted by a microscope and the ratio to the totalnumber of cells of neutrophils, eosinophils, macrophages and lymphocyteswas obtained and the number of cells per RL was calculated on the basisof this ratio.

[0422] (6) Statistical Analysis

[0423] The obtained test results were shown by mean values and standarddeviations and the student's t-test was carried out. The level ofsignificance was set to 5% or less. The number of animals used in eachtest group was 6.

[0424] Results

[0425] (1) Antigen Induced Immediate and Late Asthmatic Responses

[0426] As shown in FIG. 1, with the actively sensitized guinea pigs, theairway resistance quickly increased by inhalation of “OVA” and increasedafter one minute, on average, by 475% of that before the challenge.Thereafter, the airway resistance quickly was reduced and decreased to52% after three hours. Furthermore, the airway resistance increasedagain and reached 156% after 6 hours. The area under the response curve(hereinafter referred to as “AUC”) from 4 hours to 8 hours was 466%,hr.From this, the biphasic response of the immediate asthmatic responsewhich occurred within 30 minutes after the challenge (IAR) by the “OVA”inhalation and the late asthmatic response which occurred several hours(LAR) after the challenge was recognized.

[0427] Here, when Compounds of Examples 1 and 4 were orally dosed with10 mg/kg one hour before the “OVA” challenge, each IAR (% change insRaw) was inhibited by 70% and 73%, and LAR (AUC) was inhibited by 77%and 86% compared to the control group (FIG. 2).

[0428] (2) Number of Cells in Bronchoalveolar Lavage Fluid

[0429] The results are shown in FIG. 3. In the actively sensitizedguinea pigs by the “OVA” inhalation, the total number of cells in thebronchoalveolar lavage fluid 24 hours after the antigen challenge was,on average, 6,667/μL, and the numbers of cells of macrophages,neutrophils, eosinophils and lymphocytes were, on average, 2,499, 2,487,1,622 and 59/μL, respectively.

[0430] When Compound of Example 1 was orally dosed with 10 mg/kg onehour before the “OVA” challenge, the total number of cells was, onaverage, 3,775/μL, and the numbers of cells of macrophages, neutrophils,eosinophils and lymphocytes were, on average, 1,872, 1,072, 810 and21/μL, respectively; a significant decrease in the total number of cellsand a tendency for the numbers of cells of neutrophils, eosinophils andlymphocytes to decrease compared to the control group were recognized.On the other hand, when Compound of Example 4 was orally dosed with 10mg/kg one hour before the “OVA” challenge, the total number of cellswas, on average, 4,304/μL, and the numbers of cells of macrophages,neutrophils, eosinophils and lymphocytes were, on average, 2,478, 1,062,700 and 64/μL, respectively; a significant decrease in the total numberof cells and eosinophils and a tendency for the numbers of cells ofneutrophils to decrease compared to the control group were recognized.

[0431] From the above results, both Compounds of Examples 1 and 4exhibited inhibition against the immediate and late asthmatic responsesof guinea pigs and, in addition, inhibition against the increase in thenumber of inflammatory cells in the bronchoalveolar lavage fluid andsuggested a possibility that they would become promising drugs for thetherapy of asthma in clinical trials.

Test Example 3 Action on Antigen Induced Airway Hypersensitivity inActively Sensitized Guinea Pigs

[0432] Bronchial asthma is a disease characterized by bronchialcontraction, airway hypersensitivity and infiltration of inflammatorycells into the airway. Airway hypersensitivity is a condition in whichthe airway sensitively produces a contraction response to various slightstimuli. Particularly, airway hypersensitivity is considered to be acommon feature among patients suffering from allergic bronchial asthma.This experimental system in which actively sensitized guinea pigs areused is useful as a airway hypersensitivity model.

[0433] (1) Sensitization

[0434] Guinea pigs were allowed to inhale a 1% “OVA” (Sigma Aldrich Co.,U.S.A) physiological saline for 10 minutes daily continuously for 8 dayswith the use of an ultrasonic nebulizer (“NE-U12”, Omron, Japan).

[0435] (2) Challenge

[0436] One week after the final sensitization, the guinea pigs wereallowed to inhale a 2% “OVA” physiological saline for 5 minutes.Twenty-four hours before challenge and one hour before challenge, theguinea pigs were dosed with metyrapone (10 mg/kg, Sigma-Aldrich Co.,U.S.A.) intravenously, and dosed with pyrilamine (10 mg/kg,Sigma-Aldrich Co., U.S.A.) intraperitoneally 30 minutes beforechallenge.

[0437] (3) Preparation of Test Substance and Method of Administration

[0438] Test substance (Compound of Example 4) was formed into asuspension with a 0.5% CMC-Na solution at each predeterminedconcentration. In two groups of guinea pigs, one hour before challenge,the guinea pigs of the each group were orally dosed with the suspensionof the test substance with a dose set at 10 mg/kg or 30 mg/kgrespectively and in other one group, the guinea pigs were orally dosedwith the test substance twice, 16 hours before challenge and 2 hoursbefore challenge, with a dose set at 30 mg/kg. Dexamethasone was formedinto a suspension with a 0.5% CMC-Na solution which was then dosedtwice, 16 hours before the antigen-challenge and 2 hours before theantigen-challenge, with a dose set at 10 mg/kg. For the control groupthe medium (a 0.5% CMC-Na solution) was used. The doses were all set at5 mL/kg.

[0439] (4) Measurement of Airway Resistance

[0440] The specific airway resistance (sRaw) of wake guinea pigs wasmeasured by the double flow plethysmography with the use of airwayresistance measuring equipment (“Pulmos-1”, M.I.P.S., Japan).

[0441] (5) Measurement of Airway Reactivity

[0442] For two hours, from twenty-two to twenty-six hours after theantigen challenge, the guinea pigs were placed in an animal chamber andallowed to inhale a physiological saline and acetylcholine (hereinafterreferred to as “ACh”) solutions of 0.0625, 0.125, 0.25, 0.5, 1 and 2mg/mL , respectively, in the order named, each for one minute until sRawcame to the value at least twice the baseline sRaw (sRaw after theinhalation of the physiological saline). The ACh concentration(hereinafter referred to as “PC₁₀₀ACh”) necessary for 100% increase inthe baseline sRaw was calculated from the concentration of ACh andsRaw-resistance curve.

[0443] (6) Statistical Analysis

[0444] The obtained test results were shown by mean values and standarddeviations and the student's t-test was carried out. The level ofsignificance was set to 5% or less. The number of animals used in eachtest group was 6.

[0445] Results

[0446] The results are shown in FIG. 4. In the guinea pigs activelysensitized by the “OVA” inhalation, the airway reactivity to ACh 22hours to 26 hours after the challenge of antigen-antibody reaction wasmeasured. The PC₁₀₀ACh of the control group using the medium alone was0.15 mg/mL. According to the report [Fuchikami, J-I, et al,Pharmacological study on antigen induced immediate and late asthmaticresponses in actively sensitized guinea-pigs, Jap, J. Pharmacol., 71,pl96 (1996)] on the same system, the PC₁₀₀ACh of guinea pigs challengedby a physiological saline in the guinea pigs actively sensitized by the“OVA” inhalation was, on average, 1.20 mg/mL and thus, in the controlgroup of the present experiment the antigen induced airwayhypersensitivity was clearly recognized. Further, when dexamethasoneused as the positive control was orally dosed with 10 mg/kg 16 hours and2 hours before the “OVA” challenge, the PC100ACh was 1.14 mg/mL, theairway hypersensitivity was significantly inhibited compared to thecontrol group. On the other hand, when Compound of Example 4 was orallydosed with 10 and 30 mg/mL, respectively, one hour before the “OVA”challenge, the PC₁₀₀ACh was 0.59 and 1.63 mg/mL, respectively, andexhibited a dose-dependent inhibition. Further, when Compound of Example4 was orally dosed with 30 mg/kg twice 16 hours and 2 hours before the“OVA” challenge, the PC₁₀₀ACh was 1.24 mg/mL, and the airwayhypersensitivity was significantly inhibited compared to the controlgroup.

[0447] From the above results, it is clear that Compound of Example 4has a strong inhibition against the hypersensitivity in sensitizedguinea pigs and, and it has suggested a possibility that Compound ofExample 4 would become a promising anti-asthmatic drug even in clinicaltrials.

Test Example 4

[0448] Toxicity Study of Two-Week Repeated-Dose Oral Administration withRats

[0449] In order to study the toxicity by repeated-dose administration ofcompounds, the compounds were dosed orally to Sprague-Dawley line rats(three male rats per group) with 0, 125 and 500 mg/kg/day (a 0.5 w/v %CMC-Na solution) repeatedly for two weeks. The results are shown inTable 20. TABLE 20 Example No. Results Comparative Kidney damage wereobserved with Example 125 mg/kg or more. Example 1 No abnormalities wererecognized in any dosed group. Example 4 Tendency to weight inhibitionwas recognized in the group with 500 mg/kg.

INDUSTRIAL APPLICABILITY

[0450] The compounds of the present invention have a wide range ofpharmacological actions such as an excellent tracheal smooth musclerelaxing action, an inhibition of airway hypersensitivity and aninhibition of infiltration of inflammatory cells into the airway andalso high safety and accordingly, are very promising as drugs.

1. A compound represented by formula (1),

wherein when the X—Y bond is a single bond, X and Y, which may be thesame or different, are each independently any one selected from thegroup consisting of CW₁W₂ (wherein W, and W₂, which may be the same ordifferent, are each independently any one of a hydrogen atom, a halogen,a hydroxyl group, a lower alkyl group, a substituted lower alkyl group,a lower alkoxy group, a cycloalkyl group and a cycloalkenyl group), C═O,and C═NOW₃ (wherein W₃ is a hydrogen atom or a lower alkyl group); whenthe X—Y bond is a double bond, X and Y, which may be the same ordifferent, are each independently CW₄ (wherein W₄ is any one of ahydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, asubstituted lower alkyl group, a lower alkoxy group and an acyloxygroup); Z is any one selected from O, S, S═O and SO₂; U is C or N; R₁ toR₄, which may be the same or different, are each independently any oneselected from the group consisting of a hydrogen atom, a lower alkylgroup, a substituted lower alkyl group, a cycloalkyl group, asubstituted cycloalkyl group, a lower alkenyl group, a substituted loweralkenyl group, a lower alkynyl group, a substituted lower alkynyl group,a halogen, a lower alkylcarbonyl group, a substituted loweralkylcarbonyl group, a trihalomethyl group, V₁W₅ (wherein V₁ is any oneof O, S, S═O and SO₂; and W₅ is any one of a hydrogen atom, a loweralkyl group, a substituted lower alkyl group, a lower alkylcarbonylgroup and a substituted lower alkylcarbonyl group, an acyloxy group anda trihalomethyl group), a nitro group, an amino group, a substitutedamino group, a cyano group, an acyl group, an acylamino group, asubstituted acyl group, a substituted acylamino group, an aromatic ring,a substituted aromatic ring, a heterocycle and a substituted heterocycle(when U is N, R₄ does not exist in some cases); R₅ to R₈, which may bethe same or different, are each independently any one selected from thegroup consisting of a hydrogen atom, a lower alkyl group, a substitutedlower alkyl group, a lower alkenyl group, a substituted lower alkenylgroup, a lower alkynyl group, a substituted lower alkynyl group, ahalogen, a lower alkylcarbonyl group, a substituted lower alkylcarbonylgroup, a trihalomethyl group, V₂W₇ (wherein V₂ is any one selected fromO, S, S═O and SO₂; and W₇ is any one selected from a hydrogen atom, alower alkyl group, a substituted lower alkyl group, a loweralkylcarbonyl group, a substituted lower alkylcarbonyl group and atrihalomethyl group), a nitro group, an amino group, a substituted aminogroup, an acylamino group, an aromatic ring, a substituted aromaticring, a heterocycle and a substituted heterocycle; provided that atleast one of R₅ to R₈ is a hydroxyl group [provided that at least one ofR₅, R₇ or R₈ is a hydroxy group when the X—Y bond is CH(C₂H₅)CO and R₆is a hydroxyl group] when X is CHW₀, CW₀W₀ or CW₀ (wherein W₀ is any oneselected from a lower alkyl group and a substituted lower alkyl group)and at least one of R₅ to R₈ is a hydroxyl group and, at the same time,at least one of the other R₅ to R₈ is a group of OR (wherein R is anyone selected from the group consisting of a hydrogen atom, a lower alkylgroup, a substituted lower alkyl group, a lower alkylcarbonyl group anda substituted lower alkylsilyl group) when X is other than CHW₀, CW₀W₀or CW₀ (wherein W₀ is any one selected from a lower alkyl group and asubstituted lower alkyl group); in addition, when the X-Y is CH₂CH₂,CHBrCH₂, CH₂CO, CHBrCO, CH═CH, CH═COCOCH₃ or CH═COCH₃, at least one ofR₁ to R₄ is an aromatic ring, a substituted aromatic ring, a heterocycleor a substituted heterocycle (provided that when both R₆ and R₇ arehydroxyl groups, any one of R₁ to R₄ is not a phenyl group); or at leastone of R₁ to R₄ is SW₈ (wherein W₈ is a lower alkyl group or asubstituted lower alkyl group) or S(O)W₉ (wherein Wg is a lower alkylgroup or a substituted lower alkyl group) (provided that R₇ is ahydrogen atom when Z is O); or R₂ is either a lower alkyl group or asubstituted lower alkyl group and, at the same time, R₈ is a hydroxylgroup (provided that the number of carbon atoms of the lower alkyl groupis 3 or more when Z is O); or at least one of R₁ to R₄ is a loweralkylcarbonyl group (provided that the number of carbon atoms of thelower alkyl group is 3 or more), a cycloalkylcarbonyl group or acycloalkenylcarbonyl group and, at the same time, R₈ is a hydroxylgroup; or at least one of R₁ to R₄ is a cyano group; or at least one ofR₁ to R₄ is a halogen and, at the same time, Z is any one of S, S═O andSO₂; or R₅ and R₆ are hydroxyl groups and, at the same time, Z is S; orat least one of R₁ to R₄ is —C(═NOR)CH₃ (wherein R is a hydrogen atom ora lower alkyl group), an optical isomer thereof, a conjugate thereof ora pharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1, wherein R₆ is a hydroxyl group.
 3. The compound according toclaim 1, wherein R₆ and R₇ are hydroxyl groups.
 4. The compoundaccording to claim 1, wherein R₆ and R₈ are hydroxyl groups.
 5. Thecompound according to claim 1, wherein R₅ and R₆ are hydroxyl groups. 6.The compound according to any one of claims 1 to 5, wherein the X—Y bondis a single bond and X is CW₁W₂ (wherein at least one of W₁ and W₂ isany one selected from a lower alkyl group, a substituted lower alkylgroup, a cycloalkyl group and a cycloalkenyl group) or the X—Y bond is adouble bond and X is CW (wherein W is any one selected a lower alkylgroup, a substituted lower alkyl group, a cycloalkyl group and acycloalkenyl group).
 7. The compound according to any one of claims 1 to6, wherein Y is CO.
 8. The compound according to claim 6 or claim 7,wherein the lower alkyl group is any one of a methyl group, an ethylgroup, a n-propyl group, an isopropyl group, an n-butyl group, asec-butyl group, an isobutyl group and a tert-butyl group.
 9. Thecompound according to any one of claims 1 to 5, wherein R₂ or R₃ is anyone of a heterocycle, a substituted heterocycle, an aromatic ring and asubstituted aromatic ring.
 10. The compound according to any one ofclaims 1 to 5, wherein the heterocyle is an aromatic heterocyle.
 11. Thecompound according to any one of claims 1 to 5, wherein R₂ or R₃ is SW₈(wherein W₈ is a lower alkyl group or a substituted lower alkyl group)or S(O)W₉ (wherein W₉ is a lower alkyl group or a substituted alkylgroup).
 12. The compound according to claim 11, wherein the lower alkylgroup is any one of a methyl group, an ethyl group, a n-propyl group, anisopropyl group, an n-butyl group, a sec-butyl group, an isobutyl groupand a tert-butyl group.
 13. The compound according to any one of claims1 to 12, wherein Z is S.
 14. The compound according to claim 1 which is7,8-dihydroxy-11-ethyl-10,11-dihydrodibenzo[b,f]thiepin-10-one.
 15. Thecompound according to claim 1 which is11-diethyl-7,8-dihydroxy-10,11-dihydrodibenzo[b,f]thiepin-10-one. 16.The compound according to claim 1 which is7,9-dihydroxy-2-methylthio-10,11-dihydrodibenzo[b,f]thiepin-10-one. 17.A method of preparing a compound represented by formula (1),

wherein when the X—Y bond is a single bond, X and Y, which may be thesame or different, are each independently any one selected from thegroup consisting of CW₁W₂ (wherein W₁ and W₂, which may be the same ordifferent, are each independently any one of a hydrogen atom, a halogen,a hydroxyl group, a lower alkyl group, a substituted lower alkyl group,a lower alkoxy group, a cycloalkyl group and a cycloalkenyl group), C═O,and C═NOW₃ (wherein W₃ is a hydrogen atom or a lower alkyl group); whenthe X—Y bond is a double bond, X and Y, which may be the same ordifferent, are each independently CW₄ (wherein W₄ is any one of ahydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, asubstituted lower alkyl group, a lower alkoxy group and an acyloxygroup); Z is any one selected from O, S, S═O and SO₂; U is C or N; R₁ toR₄, which may be the same or different, are each independently any oneselected from the group consisting of a hydrogen atom, a lower alkylgroup, a substituted lower alkyl group, a cycloalkyl group, asubstituted cycloalkyl group, a lower alkenyl group, a substituted loweralkenyl group, a lower alkynyl group, a substituted lower alkynyl group,a halogen, a lower alkylcarbonyl group, a substituted loweralkylcarbonyl group, a trihalomethyl group, V₁W₅ (wherein V₁ is any oneof O, S, S═O and SO₂; and W₅ is any one of a hydrogen atom, a loweralkyl group, a substituted lower alkyl group, a lower alkylcarbonylgroup and a substituted lower alkylcarbonyl group, an acyloxy group anda trihalomethyl group), a nitro group, an amino group, a substitutedamino group, a cyano group, an acyl group, an acylamino group, asubstituted acyl group, a substituted acylamino group, an aromatic ring,a substituted aromatic ring, a heterocycle and a substituted heterocycle(when U is N, R₄ does not exist in some cases); R₅ to R₈, which may bethe same or different, are each independently any one selected from thegroup consisting of a hydrogen atom, a lower alkyl group, a substitutedlower alkyl group, a lower alkenyl group, a substituted lower alkenylgroup, a lower alkynyl group, a substituted lower alkynyl group, ahalogen, a lower alkylcarbonyl group, a substituted lower alkylcarbonylgroup, a trihalomethyl group, V₂W₇ (wherein V₂ is any one selected fromO, S, S═O and SO₂; and W₇ is any one selected from a hydrogen atom, alower alkyl group, a substituted lower alkyl group, a loweralkylcarbonyl group, a substituted lower alkylcarbonyl group and atrihalomethyl group), a nitro group, an amino group, a substituted aminogroup, an acylamino group, an aromatic ring, a substituted aromaticring, a heterocycle and a substituted heterocycle; provided that atleast one of R₅ to R₈ is a hydroxyl group [provided that at least one ofR₅, R₇ or R₈ is a hydroxy group when the X—Y bond is CH(C₂H₅)CO and R₆is a hydroxyl group] when X is CHW₀, CW₀W₀ or CW₀ (wherein W₀ is any oneselected from a lower alkyl group and a substituted lower alkyl group)and at least one of R₅ to R₈ is a hydroxyl group and, at the same time,at least one of the other R₅ to R₈ is a group of OR (wherein R is anyone selected from the group consisting of a hydrogen atom, a lower alkylgroup, a substituted lower alkyl group, a lower alkylcarbonyl group anda substituted lower alkylsilyl group) when X is other than CHW₀, CW₀W₀or CW₀ (wherein W₀ is any one selected from a lower alkyl group and asubstituted lower alkyl group); in addition, when the X—Y is CH₂CH₂,CHBrCH₂CH₂CO, CHBrCO, CH═CH, CH═COCOCH₃ or CH═COCH₃, at least one of R₁to R₄ is an aromatic ring, a substituted aromatic ring, a heterocycle ora substituted heterocycle (provided that when both R₆ and R₇ arehydroxyl groups, any one of R₁ to R₄ is not a phenyl group); or at leastone of R₁ to R₄ is SW₈ (wherein W₈ is a lower alkyl group or asubstituted lower alkyl group) or S(O)W₉ (wherein W₉ is a lower alkylgroup or a substituted lower alkyl group) (provided that R₇ is ahydrogen atom when Z is O); or R₂ is either a lower alkyl group or asubstituted lower alkyl group and, at the same time, R₈ is a hydroxylgroup (provided that the number of carbon atoms of the lower alkyl groupis 3 or more when Z is O); or at least one of R₁ to R₄ is a loweralkylcarbonyl group (provided that the number of carbon atoms of thelower alkyl group is 3 or more), a cycloalkylcarbonyl group or acycloalkenylcarbonyl group and, at the same time, R₈ is a hydroxylgroup; or at least one of R₁ to R₄ is a cyano group; or at least one ofR₁ to R₄ is a halogen and, at the same time, Z is any one of S, S═O andSO₂; or R₅ and R₆ are hydroxyl groups and, at the same time, Z is S; orat least one of R₁ to R₄ is —C(═NOR)CH₃ (wherein R is a hydrogen atom ora lower alkyl group), an optical isomer thereof, a conjugate thereof ora pharmaceutically acceptable salt thereof, which comprises, in anyorder, the reaction steps of {circle over (1)} bonding a ring A to aring C by the Ullmann reaction as shown in formula 2 and {circle over(2)} bonding a ring A to a ring C by the Friedel-Crafts reaction orphotoreation as shown in formula 3,

wherein Q, S and W are each any substitutent; U is C or N; one of X andY is an leaving group and the other is a nucleophilic group; and Z isany one of O, S, SO and SO₂.
 18. The method according to claim 17further comprising at least one step of the step of carbon atomincreasing reaction, the step of conversion reaction of a substituent,the step of introduction reaction of a substituent, the step of removalof the protection of a substituent, the step of forming a salt and thestep of performing optical resolution.
 19. A pharmaceutical compositioncomprising an effective amount of the compound described in any one ofclaims 1 to 16 and a pharmaceutically acceptable carrier or diluent. 20.The pharmaceutical composition according to claim 19 which utilizes thetracheal smooth muscles relaxing action of the compound.
 21. Thepharmaceutical composition according to claim 19 which utilizes theinhibitiory effect on airway hypersensitivity of the compound.
 22. Thepharmaceutical composition according to claim 19 which utilizes theinhibitiory effect on inflammatory cells infiltration of the compound.23. The pharmaceutical composition according to claim 19 which is usedas the antiasthmatic drug.
 24. A compound of the following formula,

wherein Q is a lower alkyl group,an optical isomer thereof or a saltthereof.
 25. A compound of the following formula,

wherein Q is a lower alkyl group; and Q₁ to Q₅, which may be the same ordifferent, are each independently any one selected from a hydrogen atom,a lower alkoxy group and a hydroxyl group, an optical isomer thereof ora salt thereof.